Schaik, R.H.N. van

Prospective Multicenter Evaluation of the Beckman Coulter Prostate Health Index Using WHO Calibration (Article)

2013-03-22T00:00:00Z

Purpose: Reported prostate specific antigen values may differ substantially among assays using Hybritech® or WHO standardization. The Beckman Coulter® Prostate Health Index and [-2]proPSA are newly approved serum markers associated with prostate cancer risk and aggressiveness. We studied the influence of assay standardization on these markers. Materials and Methods: Prostate specific antigen, percent free prostate specific antigen and [-2]proPSA were measured using Hybritech calibration in 892 men from a prospective, multicenter study undergoing prostate biopsy. We calculated the Prostate Health Index using the equation, ([-2]proPSA/free prostate specific antigen) × sqrt(P)SA. Index performance characteristics for prostate cancer detection were then determined using recalculated WHO calibration prostate specific antigen values. Results: The median Prostate Health Index was significantly higher in men with prostate cancer than in those with negative biopsies using WHO values (47.4 vs 39.8, p <0.001). The index offered improved discrimination of prostate cancer detection on biopsy (AUC 0.704) compared to percent free or total prostate specific antigen using the WHO calibration. Conclusions: The Prostate Health Index can be calculated using Hybritech or WHO standardized assays. It significantly improved prediction of the biopsy outcome over that of percent free or prostate specific antigen alone.

Doubt about the feasibility of preemptive genotyping (Article)

2013-03-01T00:00:00Z

CYP3A4 intron 6 C>T SNP (CYP3A4*22) encodes lower CYP3A4 activity in cancer patients, as measured with probes midazolam and erythromycin (Article)

2013-01-01T00:00:00Z

Aim: The CYP3A4*22 allele was recently reported to be associated with reduced CYP3A4 activity. We investigated the impact of this allele on the metabolism of the CYP3A-phenotyping probes, midazolam (MDZ) and erythromycin. Patients & methods: Genomic DNA from 108 cancer patients receiving intravenous MDZ and 45 undergoing the erythromycin breath test was analyzed for CYP3A4*22 (rs35599367 C>T) and CYP3A5*3. Results: The MDZ metabolic ratio (1́-OH-MDZ:MDZ) was 20.7% (95% CI: -36.2 to -6.2) lower for CYP3A4*22 carriers compared with CYP3A4*1/*1 patients (p = 0.01). Combining CYP3A4*22 and CYP3A5*3 genotypes showed a 38.7% decrease (95% CI: -50.0 to -27.4; p < 0.001) in 1́-OH-MDZ:MDZ for poor (CYP3A4*22-CYP3A5*3/*3) and 28.0% (95% CI: -33.3 to -22.6; p < 0.001) for intermediate (CYP3A4*1/*1-CYP3A5*3/*3) metabolizers, compared with extensive (CYP3A4*1/*1-CYP3A5*1) CYP3A metabolizers. CYP3A4 erythromycin N-demethylation activity was 40% lower in CYP3A4*22 carriers compared with CYP3A4*1/*1 patients (p = 0.032). Conclusion: The CYP3A4*22 allele is associated with decreased CYP3A4-mediated metabolism, as verified by CYP3A-phenotyping probes. Original submitted 10 September 2012; Revision submitted 3 December 201.

Reply to F.L. Opdam et al (Article)

2012-02-01T00:00:00Z

The interactions of age, genetics, and disease severity on tacrolimus dosing requirements after pediatric kidney and liver transplantation (Article)

2011-12-01T00:00:00Z

Purpose: In children, data on the combined impact of age, genotype, and disease severity on tacrolimus (TAC) disposition are scarce. The aim of this study was to evaluate the effect of these covariates on tacrolimus dose requirements in the immediate post-transplant period in pediatric kidney and liver recipients. Methods: Data were retrospectively collected describing tacrolimus disposition, age, CYP3A5 and ABCB1 genotype, and pediatric risk of mortality (PRISM) scores for up to 14 days post-transplant in children receiving liver and renal transplants. Initial TAC dosing was equal in all patients and adjusted using therapeutic drug monitoring. We determined the relationship between covariates and tacrolimus disposition. Results: Forty-eight kidney and 42 liver transplant recipients (median ages 11.5 and 1.5 years, ranges 1.5-17.7 and 0.05-14.8 years, respectively) received TAC post-transplant. In both transplant groups, younger children (<5 years) needed higher TAC doses than older children [kidney: 0.15 (0.07-0.35) vs. 0.09 (0.02-0.20) mg/kg/12h, p = 0.046, liver: 0.12 (0.04-0.32) vs. 0.09 (0.01-0.18) mg/kg/12h, p = 0.038]. In kidney but not liver transplants, CYP3A5 expressors needed significantly higher TAC doses than nonexpressors [0.15 (0.07-0.20) vs. 0.09 (0.02-0.35) mg/kg/12h, P = 0.001]. In these patients, age and CYP3A5 genotype were independently associated with TAC dosing requirement. In liver, but not kidney transplant patients, homozygous ABCB1 T-T-T haplotype carriers needed higher TAC doses than noncarriers [0.26 (0.15-0.32) vs. 0.11 (0.01-0.25) mg/kg/12h, p = 0.013]. Conclusion: CYP3A5 genotype may explain variation in tacrolimus disposition early after transplant in pediatric kidney recipients, independent of age-related variation. In contrast, in pediatric liver recipients, variation in tacrolimus disposition appears related to age and ABCB1 genotype. These findings illustrate the importance of the interplay among age, genotype, and transplant organ on tacrolimus disposition.

Age and CYP3A5 genotype affect tacrolimus dosing requirements after transplant in pediatric heart recipients (Article)

2011-12-01T00:00:00Z

Background: Tacrolimus is one of the commonly used immunosuppressive drugs for pediatric heart transplants. Large variation exists in pharmacokinetics during the direct post-transplant period, resulting in an increased risk of adverse events. Limited data are available on the interaction of age, CYP3A5 and ABCB1 genotype, and disease severity on the variation in disposition and outcome in pediatric heart transplant recipients. Method: We studied the relationship between age and CYP3A5 and ABCB1 genotype and the Pediatric Risk of Mortality (PRISM) score on tacrolimus dose (mg/kg), steady-state trough concentrations, and concentration/dose ratio, as well as rejection and renal function for 14 days after heart transplant in children. Results: Tacrolimus was administered to 39 children (median age, 6.0 years) after transplant. A correlation was found between the age at the time of transplant and the tacrolimus dosing requirements (rs= 0.447, p = 0.004) and the concentration/dose ratio (rs= 0.351, p = 0.029). CYP3A5 expressors required median (interquartile range) higher doses of tacrolimus (0.14 [0.09] vs 0.06 [0.04] mg/kg/12 hours, p = 0.001), and had lower concentration/dose ratios (45.34 [44.54] vs 177.78 [145.38] ng/ml per mg/kg/12 hours, p < 0.0001). This relationship was not seen with the ABCB1 genotype. Age and CYP3A5 genotype predicted the tacrolimus dosing requirements as well as the concentration/dose ratio (R2= 0.351, p = 0.001 and R2= 0.521, p < 0.001). No relationship was found between any of the CYP3A5 or ABCB1 genotypes and the estimated glomerular filtration rate. Conclusion: Younger age and CYP3A5 expressor genotype were independently associated with higher dosing requirements and lower tacrolimus concentration/dose ratios.

Novel CYP3A4 intron 6 single nucleotide polymorphism is associated with simvastatin-mediated cholesterol reduction in the Rotterdam Study (Article)

2011-12-01T00:00:00Z

Objectives: CYP3A4 is involved in the oxidative metabolism of many drugs and xenobiotics including the HMG-CoA reductase inhibitor simvastatin. The objective of this study was to investigate whether a new CYP3A4 functional single nucleotide polymorphism (SNP) in intron 6 (CYP3A4*22) modifies the effect of simvastatin on total cholesterol (TOTc) or LDL cholesterol (LDLc) reduction in a population-based cohort study. Methods: In a total of 80 incident simvastatin users, the association between the CYP3A4 intron 6 C>T SNP (rs35599367) and reduction in cholesterol levels was analyzed using linear regression analysis and adjusting for potential confounding factors. Results: The CYP3A4*22 allele was associated with a trend towards a stronger simvastatin lipid-lowering response, as reflected by the greater reduction in both TOTc and LDLc levels when compared with homozygous wild type. We observed that the CYP3A4*22 allele carriers had an increased reduction in TOTc and LDLc:-0.25 mmol/l (95% confidence interval [CI95%]=[-0.52; 0.01], P=0.058) and-0.29 mmol/l (CI95%=[-0.58; 0.01], P=0.054) when compared with homozygous CC. When we adjusted the model for potential confounding factors, the corresponding reduction in TOTc was-0.31 mmol/l (CI95%=[-0.59;-0.04], P=0.028) and for LDLc-0.34 mmol/l (CI95%=[-0.66;-0.02], P=0.034) greater for CYP3A4*22 allele carriers when compared with homozygotes wild type. Conclusion: The CYP3A4*22 intron 6 SNP T-variant allele was associated with reduced CYP3A4 activity, resulting in a better lipid lowering response to simvastatin, when data were adjusted for confounding factors. This observation is a step towards the clarification of the reasons of interindividual variability in statins response and may potentially lead to improved tailoring of simvastatin therapy.

ATP-binding cassette transporters as pharmacogenetic biomarkers for kidney transplantation (Article)

2011-10-27T00:00:00Z

Immunosuppressive drugs used in organ transplantation are highly effective in preventing acute rejection. However, the clinical use of these drugs is complicated by the fact that they display highly variable pharmacokinetics and pharmacodynamics between individual patients. The influence of genetic variation on the interindividual variability in immunosuppressive drug disposition, efficacy, and toxicity has been explored in recent years. The polymorphically-expressed ATP-binding cassette (ABC) transporter proteins, in particular ABCB1 and ABCC2, have been investigated extensively because they play an important role in the absorption, distribution and elimination of many immunosuppressive drugs in use today. From these studies it can be concluded that polymorphisms in ABCB1 and ABCC2 have no consistent effect on immunosuppressant pharmacokinetics and toxicity although polymorphisms in ABCB1 appear to be related to the risk of developing calcineurin inhibitor-related nephrotoxicity. However, the latter needs to be replicated before an individual's ABCB1 genotype can become a useful marker that is applied in clinical practice. Future studies evaluating the influence of ABC transporter gene polymorphisms should explore the relationship with intracellular rather than systemic drug concentrations further in well-designed clinical studies. Until then, single-nucleotide polymorphisms in ABC transporter genes are not suitable to act as biomarkers for solid organ transplantation.

Dextromethorphan as a phenotyping test to predict endoxifen exposure in patients on tamoxifen treatment (Article)

2011-08-20T00:00:00Z

Purpose: Tamoxifen, a widely used agent for the prevention and treatment of breast cancer, is mainly metabolized by CYP2D6 and CYP3A to form its most abundant active metabolite, endoxifen. Interpatient variability in toxicity and efficacy of tamoxifen is substantial. Contradictory results on the value of CYP2D6 genotyping to reduce the variable efficacy have been reported. In this pharmacokinetic study, we investigated the value of dextromethorphan, a known probe drug for both CYP2D6 and CYP3A enzymatic activity, as a potential phenotyping probe for tamoxifen pharmacokinetics. Methods: In this prospective study, 40 women using tamoxifen for invasive breast cancer received a single dose of dextromethorphan 2 hours after tamoxifen intake. Dextromethorphan, tamoxifen, and their respective metabolites were quantified. Exposure parameters of all compounds were estimated, log transformed, and subsequently correlated. Results: A strong and highly significant correlation (r=-0.72; P < .001) was found between the exposures of dextromethorphan (0 to 6 hours) and endoxifen (0 to 24 hours). Also, the area under the plasma concentration-time curve of dextromethorphan (0 to 6 hours) and daily trough endoxifen concentration was strongly correlated (r = -0.70; P < .001). In a single patient using the potent CYP2D6 inhibitor paroxetine, the low endoxifen concentration was accurately predicted by dextromethorphan exposure. Conclusion: Dextromethorphan exposure after a single administration adequately predicted endoxifen exposure in individual patients with breast cancer taking tamoxifen. This test could contribute to the personalization and optimization of tamoxifen treatment, but it needs additional validation and simplification before being applicable in future dosing strategies.

CYP3A5, ABCB1, and SLCO1B1 polymorphisms and pharmacokinetics and virologic outcome of lopinavir/ritonavir in HIV-infected children (Article)

2011-08-01T00:00:00Z

Objective: CYP3A5, MDR1 (ABCB1), and OATP1 (SLCO1B1) polymorphisms have been associated with variability in the pharmacokinetics (PK) of protease inhibitors. The aim of this study was to investigate the influence of CYP3A5 A6986G, ABCB1 (C3435T and G2677T), and SLCO1B1 (T521C and A388AG) polymorphisms on the PK and virologic outcome of lopinavir/ritonavir (LPV/RTV) in HIV-infected children. Design and Methods: We conducted a prospective cohort study in children (4-18 years old) on stable antiretroviral therapy with LPV/RTV. CYP3A5, ABCB1, and SLCO1B1 genotypes were determined using polymerase chain reaction amplification with allelic discrimination assays. The 12-hour plasma area under the concentration- time curves (AUC) and clearances (CL) of LPV and RTV were estimated using noncompartmental models. HIV RNAviral load was evaluated every 12 weeks for a total study period of 52 weeks. Analysis of covariance models with adjustment for age and adherence and allometric adjustment of CL were used to assess associations between studied polymorphisms and AUC, CL, and HIV RNA. Results: Fifty children (median age 11.2 years) were enrolled. Allele frequencies of the genotypes studied were in Hardy-Weinberg equilibrium. There was no statistically significant association between LPV or RTV AUC or CL, and CYP3A5, ABCB1, or SLCO1B1 A388G polymorphisms. There was a significant association between SLCO1B1 T521C genotype and increased LPV AUC (P = 0.042) and a nearly significant association with decreased LPV CL (P = 0.063). None of the studied polymorphisms, including SLCO1B1 T521C, were associated with virologic outcome during 52 weeks of study follow-up. Conclusions: There was no statistically significant influence of the CYP3A5, ABCB1, or SLCO1B1 A388AG polymorphisms on the PK and virologic outcome of LPV/RTV in HIV-infected children. SLCO1B1 T521C polymorphism was significantly associated with an increase in LPVAUC but was not associated with undetectable HIV RNA during the study period. Copyright

The CYP2C19*2 genotype predicts tamoxifen treatment outcome in advanced breast cancer patients (Article)

2011-08-01T00:00:00Z

Aims: Tamoxifen is metabolized by cytochrome P450s, with an important role for CYP2D6. Recently, we demonstrated in 80 patients that CYP2C19*2 is associated with increased survival in breast cancer patients using tamoxifen. Here, we aimed to confirm this in a large group of 499 patients. Materials & methods: A total of 499 estrogen receptor-positive primary breast tumor specimens of advanced disease patients treated with first-line tamoxifen were genotyped for CYP2C19*2 and 17 variant alleles, with primary end point time-to-treatment failure (TTF). Effects of CYP2C19, independent of treatment, were analyzed in 243 primary systematic untreated patients. Results: CYP2C19*2 hetero-and homozygote patients combined showed significantly longer TTFs (hazard ratio [HR]: 0.72; 95% CI: 0.57-0.90; p = 0.004). In multivariate analysis, including CYP2D6*4 status, CYP2C19*2 remained independently associated with TTF (HR: 0.73; 95% CI: 0.58-0.91; p = 0.007). In untreated patients, the CYP2C19*17 allele was significantly associated with a longer disease-free interval (HR: 0.66; 95%CI: 0.46-0.95; p = 0.025). Conclusion: CYP2C19 genotyping is potentially important for tamoxifen therapy for advanced disease and for breast cancer prognosis.

CYP3A5 genotype is not related to the intrapatient variability of tacrolimus clearance (Article)

2011-06-01T00:00:00Z

Background: The risk of long-term chronic allograft nephropathy and graft loss after kidney transplantation is increased in patients with a high intrapatient variability of tacrolimus (Tac) clearance. Methods: To test whether this intrapatient variability is associated with an individual's CYP3A5 genotype, we measured the intrapatient variability in Tac clearance in a cohort of 208 kidney transplant recipients treated with Tac and mycophenolate mofetil. Results: Tac dose requirement was significantly higher in patients expressing CYP3A5. However, intraindividual variability of Tac clearance was not related to CYP3A5 genotype. Conclusions: Intraindividual variability in Tac clearance is not related to CYP3A5 genotype. Other factors, including patient adherence, may explain the variability in Tac clearance within an individual patient over time. Copyright

Pharmacogenetics: From bench to byte an update of guidelines (Article)

2011-05-01T00:00:00Z

Currently, there are very few guidelines linking the results of pharmacogenetic tests to specific therapeutic recommendations. Therefore, the Royal Dutch Association for the Advancement of Pharmacy established the Pharmacogenetics Working Group with the objective of developing pharmacogenetics-based therapeutic (dose) recommendations. After systematic review of the literature, recommendations were developed for 53 drugs associated with genes coding for CYP2D6, CYP2C19, CYP2C9, thiopurine-S-methyltransferase (TPMT), dihydropyrimidine dehydrogenase (DPD), vitamin K epoxide reductase (VKORC1), uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), HLA-B44, HLA-B*5701, CYP3A5, and factor V Leiden (FVL).

A multicenter study of [-2]pro-prostate specific antigen combined with prostate specific antigen and free prostate specific antigen for prostate cancer detection in the 2.0 to 10.0 ng/ml prostate specific antigen range (Article)

2011-05-01T00:00:00Z

Purpose: Prostate specific antigen and free prostate specific antigen have limited specificity to detect clinically significant, curable prostate cancer, leading to unnecessary biopsy, and detection and treatment of some indolent tumors. Specificity to detect clinically significant prostate cancer may be improved by [-2]pro-prostate specific antigen. We evaluated [-2]pro-prostate specific antigen, free prostate specific antigen and prostate specific antigen using the formula, ([-2]pro-prostate specific antigen/free prostate specific antigen × prostate specific antigen1/2) to enhance specificity to detect overall and high grade prostate cancer. Materials and Methods: We enrolled 892 men with no history of prostate cancer, normal rectal examination, prostate specific antigen 2 to 10 ng/ml and 6-core or greater prostate biopsy in a prospective multi-institutional trial. We examined the relationship of serum prostate specific antigen, free-to-total prostate specific antigen and the prostate health index with biopsy results. Primary end points were specificity and AUC using the prostate health index to detect overall and Gleason 7 or greater prostate cancer on biopsy compared with those of free-to-total prostate specific antigen. Results: In the 2 to 10 ng/ml prostate specific antigen range at 80% to 95% sensitivity the specificity and AUC (0.703) of the prostate health index exceeded those of prostate specific antigen and free-to-total prostate specific antigen. An increasing prostate health index was associated with a 4.7-fold increased risk of prostate cancer and a 1.61-fold increased risk of Gleason score greater than or equal to 4 + 3 = 7 disease on biopsy. The AUC of the index exceeded that of free-to-total prostate specific antigen (0.724 vs 0.670) to discriminate prostate cancer with Gleason 4 or greater + 3 from lower grade disease or negative biopsy. Prostate health index results were not associated with age and prostate volume. Conclusions: The prostate health index may be useful in prostate cancer screening to decrease unnecessary biopsy in men 50 years old or older with prostate specific antigen 2 to 10 ng/ml and negative digital rectal examination with minimal loss in sensitivity.

Pharmacogenomics and personalized medicine in clinical practice (Article)

2011-05-01T00:00:00Z

The Santorini Conference on prospective biology, genomics and pharmacogenomics occurs every 2 years. On 30 September to 2nd October 2010, the fifth meeting in this series took place in Santorini, Greece. This conference has established a tradition of organizing a workshop each time to address the most recent developments and key issues in pharmacogenomics. This year, the workshop was chaired by Bryan Dechairo and Alain Huriez, and was titled Pharmacogenomics and personalized medicine in clinical practice'.

General maternal medication use, folic acid, the MDR1 C3435T polymorphism, and the risk of a child with a congenital heart defect (Article)

2011-03-01T00:00:00Z

Objective We sought to investigate maternal and child functional MDR1 C3435T polymorphism, periconception medication, folic acid use, and the risk of a congenital heart defect (CHD) in the offspring. Study Design MDR1 3435C>T genotyping was performed in 283 case triads (mother, father, child) and 308 control triads. Information on periconception medication and folic acid use was obtained through questionnaires. Results Mothers with MDR1 3435CT/TT genotype and using medication showed a significant association with the risk of a child with CHD (odds ratio [OR], 2.4; 95% confidence interval [CI], 1.34.3) compared to mothers with MDR1 3435CC genotype not using medication. This risk increased without folic acid use (OR, 2.8; 95% CI, 1.26.4), and decreased in folic acid users (OR, 1.7; 95% CI, 0.83.7). Children carrying the MDR1 3435CT/TT genotype and periconceptionally exposed to medication without folic acid did not show significant risks. Conclusion Mothers carrying the MDR1 3435T allele, using medication without folic acid, are at nearly 3-fold increased risk for CHD in the offspring.

OCT1 polymorphism is associated with response and survival time in anti-Parkinsonian drug users (Article)

2011-02-01T00:00:00Z

Substrates for the Organic Cation Transporter 1, encoded by the SLC22A1 gene, are metformin, amantadine, pramipexole, and, possibly, levodopa. Recently, we identified that the rs622342 A > C polymorphism is associated with the HbA1c lowering effect in metformin users. In the Rotterdam Study, we associated this polymorphism with higher prescribed doses of all anti-Parkinsonian drugs. Between the first and fifth prescriptions for levodopa, for each minor rs622342 C allele, the prescribed doses were 0.34 defined daily dose higher (95% CI 0.064, 0.62; p∈=∈0.017). The mortality ratio after start of levodopa therapy was 1.47 times higher (95% CI 1.01, 2.13; p∈=∈0.045).

Simultaneous quantification of dextromethorphan and its metabolites dextrorphan, 3-methoxymorphinan and 3-hydroxymorphinan in human plasma by ultra performance liquid chromatography/tandem triple-quadrupole mass spectrometry (Article)

2011-01-25T00:00:00Z

A rapid and sensitive ultra performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) method has been developed and validated for the simultaneous quantitative determination of dextromethorphan (DM) and its metabolites dextrorphan (DX), 3-methoxymorphinan (3MM) and 3-hydroxymorphinan (3HM), in human lithium heparinized plasma. The extraction involved a simple liquid-liquid extraction with 1ml n-butylchloride from 200μl aliquots of plasma, after the addition of 20μl 4% (v/v) ammonium hydroxide and 100μl stable labeled isotopic internal standards in acetonitrile. Chromatographic separations were achieved on an Aquity UPLC®BEH C181.7μm 2.1mm×100mm column eluted at a flow-rate of 0.250ml/min on a gradient of acetonitrile. The overall cycle time of the method was 7min, with elution times of 1.3min for DX and 3HM, 2.8min for 3MM and 2.9min for DM. The multiple reaction monitoring transitions were set at 272>215 (m/z), at 258>133 (m/z), at 258>213 (m/z) and at 244>157 (m/z) for DM, DX, 3MM and 3HM, respectively. The calibration curves were linear (r2≥0.995) over the range of 0.500-100nM with the lower limit of quantitation validated at 0.500nM for all compounds, which is equivalent to 136, 129, 129 and 122pg/ml for DM, DX, 3MM and 3HM, respectively. Extraction recoveries were constant, but ranged from 39% for DM to 83% for DX. The within-run and between-run precisions were within 11.6%, while the accuracy ranged from 92.7 to 110.6%. The applicability of the bioanalytical method was demonstrated and is currently implemented in a clinical trial to study DM as probe-drug for individualized tamoxifen treatment in breast cancer patients.

Practical recommendations for pharmacogenomics-based prescription: 2010 ESF-UB Conference on Pharmacogenetics and Pharmacogenomics (Article)

2011-01-01T00:00:00Z

The present article summarizes the discussions of the 3rd European Science Foundation-University of Barcelona (ESF-UB) Conference in Biomedicine on Pharmacogenetics and Pharmacogenomics, which was held in June 2010 in Spain. It was focused on practical applications in routine medical practice. We provide practical recommendations for ten different clinical situations, that have either been approved or not approved by regulatory agencies. We propose some comments that might accompany the results of these tests, indicating the best drug and doses to be prescribed. The discussed examples include KRAS, cetuximab, panitumumab, EGFR-gefitinib, CYP2D6-tamoxifen, TPMT-azathioprine-6- mercaptopurine, VKORC1/CYP2C9-warfarin, CYP2C19-clopidogrel, HLA-B*5701-abacavir, HLA-B*5701-flucloxacillin, SLCO1B1-statins and CYP3A5-tacrolimus. We hope that these practical recommendations will help physicians, biologists, scientists and other healthcare professionals to prescribe, perform and interpret these genetic tests.

Polymorphisms in the multidrug resistance gene MDR1 (ABCB1) predict for molecular resistance in patients with newly diagnosed chronic myeloid leukemia receiving high-dose imatinib (Article)

2010-12-23T00:00:00Z

Cytochrome P450 3A gene variation, steroid hormone serum levels and prostate cancer - The Rotterdam Study (Article)

2010-12-01T00:00:00Z

Purpose: To study if polymorphisms in genes encoding for CYP3A enzymes, that play a role in steroid hormone metabolism, affect steroid hormone serum levels and prostate cancer incidence or mortality. Methods: 3048 male participants of The Rotterdam Study were included. Prostate cancer cases and non-cases were studied for differences in baseline hormone levels with Student's t-test. General linear models were performed on different random subsets of hormone levels to study associations with genotype. Cox' proportional hazard models were used to study prostate cancer incidence and mortality among genotypes. Results: Both DHEAS sulphate as free-testosterone were significantly increased at baseline in males who developed a prostate cancer within the study period. CYP3A4 G-allele carriage was associated with lower levels of estrone sulphate (p = 0.005) and higher levels of estradiol (p = 0.04) compared to non-carriers. CYP3A5 A-allele carriage was associated with increased levels of estrone sulphate (p = 0.02). CYP3A7 G-allele carriage was associated with the highest number of significant differences in steroid hormone levels. Carriers of the allele resulting in continued enzyme expression during adulthood had decreased levels of dehydroepiandrosterone (DHEA) sulphate (p = 0.05), androstenedione (p = 0.006), estrone (p = 0.0001) and estrone sulphate (p = 0.003) compared to mean levels of these hormones in homozygous wild type carriers. CYP3A43 genotype was not associated with any of the studied hormone levels. However, carriers of the CYP3A43 G-allele showed a significant 5-fold increase in mortality among early onset diagnosed prostate cancers. Conclusion: Increased levels of free testosterone and DHEA sulphate were associated with prostate cancer incidence along the study period. Primarily the amount of CYP3A7 expression seemed to affect steroid hormone levels. Nevertheless, testosterone, a precursor of the prostate growth and differentiation stimulating dehydrotestosterone, was not influenced by CYP3A genotype. In line with this, no significant associations were observed for CYP3A genotypes and prostate cancer incidence.

On the use of prostate-specific antigen for screening of prostate cancer in European Randomised Study for Screening of Prostate Cancer (Article)

2010-11-01T00:00:00Z

Prostate-specific antigen (PSA) has been the main drive for early detection of prostate cancer (PCa), including in population-based screening as in the European Randomised Study for Screening of Prostate Cancer (ERSPC). The specificity of PSA to indicate men with biopsy detectable prostate cancer can be improved by adding information obtained by new biomarkers, such as PSA isoforms. This improvement is needed to increase the efficacy of the screening procedure for the population-based as well as the individual screening. Various PSA isoforms, kallikreins and molecular markers have been validated in various cohorts from ERSPC of men with and without PCa in order to design the optimal diagnostic procedure for screening asymptomatic men. So far, most promising results have been obtained from the analysis of free PSA, proPSA, nicked PSA and hK2. The use of free PSA in addition to total PSA reduces the number of negative sextant biopsies at a PSA cut-off level of 3 ng/ml at initial screening with 30%, at the cost of losing 10% of detectable cancers that are predominantly well differentiated on histology. Further addition of PSA isoforms and hK2 only improve ROC curves in selected samples by a maximum of 5%. Molecular markers like PCA3 and TMPRSS2 in urine do not appear to be useful but they have been assessed insufficiently so far. The level of PSA at initial screening is highly predictive for the chance of being diagnosed with PCa later on in life. The changes in PSA over time after initial screening (like PSA-velocity and PSA-doubling time) are statistically different between men with detectable cancers versus those without (PSA-doubling time 5.1 versus 6.1 years), but this does not contribute significantly to population-based screening overall. Changes in specificity need to be related to a cost efficacy evaluation in the final analysis of ERSPC.

Nucleic acid reference materials (NARMs): Definitions and issues (Article)

2010-11-01T00:00:00Z

Molecular diagnostics is one of the most rapidly growing areas of laboratory medicine. This rapid growth of clinical molecular tests has outpaced the availability and development of reference methods and reference materials. Such methods and materials are important for the development, validation, and interpretation of diagnostic methods and tests. Yet, there is a lack of harmonization between the numerous international organizations currently either certifying or defining reference materials. The objective of this position paper is to review and clarify the definition, attributes and applications for the use of reference materials in the context of molecular diagnostics.

CYP2C19*2 polymorphism is associated with increased survival in breast cancer patients using tamoxifen (Article)

2010-10-01T00:00:00Z

Abstract AIMS: Variant alleles of the CYP2C19 gene were recently associated with survival in breast cancer patients on tamoxifen therapy. CYP2C19 is one of the enzymes involved in the metabolism of tamoxifen into active metabolites. We investigated the hypothesis that CYP2C19*2 and *3 variants, known for their lack of enzyme activity, are associated with an increased breast cancer mortality rate in patients using tamoxifen. MATERIALS & METHODS: In the prospective population based Rotterdam study, the association between CYP2C19*2 carriers and breast cancer mortality was studied among 80 incident users of tamoxifen. Survival was analyzed with life tables and Cox regression analysis, with drug exposure as a time-dependent variable. Adjustments were made for calendar time, average tamoxifen dose, age, the indication for tamoxifen, CYP2D6 genotype and concomitant use of CYP2C19 inhibitors or inducers. RESULTS: In patients on tamoxifen, CYP2C19*2 carriers were associated with a significantly longer breast cancer survival rate than patients with the wild-type (hazard ratio 0.26, 95%CI: 0.08-0.87). CONCLUSION: This study suggests that CYP2C19 genotype may possibly be a predictive factor for survival in breast cancer patients using tamoxifen.

Effects of mannose-binding lectin polymorphisms on irinotecan-induced febrile neutropenia (Article)

2010-10-01T00:00:00Z

Objective. Mannose-binding lectin (MBL) is important in the innate immune response. MBL2 gene polymorphisms affect MBL expression, and genotypes yielding low MBL levels have been associated with an elevated risk for infections in hematological cancer patients undergoing chemotherapy. However, these reported associations are inconsistent, and data on patients with solid tumors are lacking. Here, we investigated the effects of MBL2 genotypes on irinotecan-induced febrile neutropenia in patients with solid tumors. Patients and Methods. Irinotecan-treated patients were genotyped for the MBL2 gene. Two promoter (550 H/L and 221 X/Y) and three exon polymorphisms (52 A/D, 54 A/B, and 57 A/C) were determined, together with known risk factors for irinotecan-induced toxicity. Neutropenia and febrile neutropenia were recorded during the first course. Results. Of the 133 patients, 28% experienced severe neutropenia and 10% experienced febrile neutropenia. No associations were found between exon polymorphisms and febrile neutropenia. However, patients with the H/H promoter genotype, associated with high MBL levels, experienced significantly more febrile neutropenia than patients with the H/L and L/L genotypes (20% versus 13% versus 5%). Moreover, patients with the HYA haplotype encountered significantly more febrile neutropenia than patients without this high MBL-producing haplotype (16% versus 4%). In the subgroup with wild-type exon polymorphisms (A/A), patients with the high MBL promoter phenotype had the highest incidence of febrile neutropenia, regardless of known risk factors. Conclusion. Patients with high MBL2 promoter genotypes and haplotypes seem more at risk for developing febrile neutropenia. If confirmed, these preliminary findings may contribute to more individualized approaches of irinotecan treatment.

The impact of CYP2D6-predicted phenotype on tamoxifen treatment outcome in patients with metastatic breast cancer (Article)

2010-09-07T00:00:00Z

Abstract BACKGROUND: Cytochrome P450 2D6 (CYP2D6) has a crucial role in the metabolic conversion of tamoxifen into the active metabolite endoxifen. In this cohort study, the effect of CYP2D6-predicted phenotype, defined as the combined effect of CYP2D6 genetic variation and concomitant use of CYP2D6-inhibiting medication, on time to breast cancer progression (TTP) and overall survival (OS) in women who use tamoxifen for metastatic breast cancer (MBC) was examined. METHODS: We selected patients treated with tamoxifen (40 mg per day) for hormone receptor-positive MBC from whom a blood sample for pharmacogenetic analysis (CYP2D6*3, *4, *5, *6, *10 and *41) was available. Patient charts (n=102) were reviewed to assess TTP and OS, and to determine whether CYP2D6 inhibitors were prescribed during tamoxifen treatment. RESULTS: OS was significantly shorter in patients with a poor CYP2D6 metaboliser phenotype, compared with extensive metabolisers (HR=2.09; P=0.034; 95% CI: 1.06-4.12). Co-administration of CYP2D6 inhibitors alone was also associated with a worse OS (HR=3.55; P=0.002; 95% CI: 1.59-7.96) and TTP (HR=2.97; P=0.008; 95% CI: 1.33-6.67) compared with patients without CYP2D6 inhibitors. CONCLUSION: CYP2D6 phenotype is an important predictor of treatment outcome in women who are receiving tamoxifen for MBC. Co-administration of CYP2D6 inhibitors worsens treatment outcome of tamoxifen and should therefore be handled with care.

Dihydropyrimidine dehydrogenase polymorphisms and fluoropyrimidine toxicity: ready for routine clinical application within personalized medicine? (Article)

2010-09-01T00:00:00Z

Fluoropyrimidines, including 5-fluorouracil (5-FU), are widely used in the treatment of solid tumors and remain the backbone of many combination regimens. Despite their clinical benefit, fluoropyrimidines are associated with gastrointestinal and hematologic toxicities, which often lead to treatment discontinuation. 5-FU undergoes complex metabolism, dihydropyrimidine dehydrogenase (DPD) being the rate-limiting enzyme of inactivation of 5-FU and its prodrugs. Several studies have demonstrated significant associations between severe toxicities by fluoropyrimidines and germline polymorphisms of DPD gene. To date, more than 30 SNPs and deletions have been identified within DPD, the majority of these variants having no functional consequences on enzymatic activity. However, the identification of deficient DPD genotypes may help identify poor-metabolizer patients at risk of developing potentially life-threatening toxicities after standard doses of fluoropyrimidines.

Polymorphisms in type i and II inosine monophosphate dehydrogenase genes and association with clinical outcome in patients on mycophenolate mofetil (Article)

2010-09-01T00:00:00Z

Background: Type I and II inosine monophosphate dehydrogenases (IMPDH) are the targets of mycophenolic acid (MPA), a widely used immunosuppressant. The aims of this study were: to check the presence of controversial polymorphisms in the IMPDH II gene; to look for new ones; and to investigate potential associations between the most frequent SNPs in both IMPDH genes and clinical outcome in renal transplant recipients. Methods: The DNA and clinical data of 456 patients from two clinical trials were collected. We sequenced the IMPDH II gene in 80 patients and we genotyped the 456 patientsÊ DNA for the IMPDH II rs4974081, rs11706052, 787C>T and the IMPDH I rs2278293 and rs2278294 SNPs, all of which were earlier reported to be potentially involved in MPA treatment related outcome. We investigated the associations of biopsy proven acute rejection (BPAR), leucopenia, cytomegalovirus infections and other infections with these IMPDH polymorphisms, as well as with demographic, biological and treatment data using multivariate analysis. Results: Many IMPDH II variant alleles referenced in Genbank were not detected and no new polymorphisms were identified. In the whole group of 456 patients, the IMPDH I rs2278294 SNP was associated with a lower risk of BPAR and a higher risk of leucopenia over the first year post-transplantation. No other IMPDH I or IMPDH II polymorphism was significantly associated with any clinical outcome. Interestingly, calcineurin inhibitor and MPA exposures below the therapeutic range increased the risk of BPAR. Cytomegalovirus infection was the factor most closely linked with leucopenia, whereas tacrolimus was associated with fewer infections than cyclosporine. Conclusion: IMPDH II genotyping may not improve MPA treatment outcome over the first year post-transplantation, in contrast to MPA and calcineurine inhibitor therapeutic drug monitoring and IMPDH I genotyping.

Prostate-Specific Antigen (PSA) Isoform p2PSA in Combination with Total PSA and Free PSA Improves Diagnostic Accuracy in Prostate Cancer Detection (Article)

2010-06-01T00:00:00Z

Background: Novel markers for prostate cancer (PCa) detection are needed. Total prostate-specific antigen (tPSA) and percent free prostate-specific antigen (%fPSA = tPSA/fPSA) lack diagnostic specificity. Objective: To evaluate the use of prostate-specific antigen (PSA) isoforms p2PSA and benign prostatic hyperplasia-associated PSA (BPHA). Design, setting, and participants: Our study included 405 serum samples from the Rotterdam arm of the European Randomised Study of Screening for Prostate Cancer and 351 samples from the Urology Department of Innsbruck Medical University. Measurements: BPHA, tPSA, fPSA, and p2PSA levels were measured by Beckman-Coulter Access Immunoassay. In addition, the Beckman Coulter Prostate Health Index was calculated: phi = (p2PSA/fPSA) × √(tPSA). Results and limitations: The p2PSA and phi levels differed significantly between men with and without PCa. No difference in BPHA levels was observed. The highest PCa predictive value in both cohorts was achieved by phi with areas under the curve (AUCs) of 0.750 and 0.709, a significant increase compared to tPSA (AUC: 0.585 and 0.534) and %fPSA (AUC: 0.675 and 0.576). Also, %p2PSA (p2PSA/fPSA) showed significantly higher AUCs compared to tPSA and %fPSA (AUC: 0.716 and 0.695, respectively). At 95% and 90% sensitivity, the specificities of phi were 23% and 31% compared to 10% and 8% for tPSA, respectively. In both cohorts, multivariate analysis showed a significant increase in PCa predictive value after addition of p2PSA to a model consisting of tPSA and fPSA (increase in AUC from 0.675 to 0.755 and from 0.581 to 0.697, respectively). Additionally, the specificity at 95% sensitivity increased from 8% to 24% and 7% to 23%, respectively. Furthermore, %p2PSA, phi, and the model consisting of tPSA and fPSA with or without the addition of p2PSA missed the least of the tumours with a biopsy or pathologic Gleason score ≥7 at 95% and 90% sensitivity. Conclusions: This study shows significant increases in PCa predictive value and specificity of phi and %p2PSA compared to tPSA and %fPSA. p2PSA has limited additional value in identifying aggressive PCa (Gleason score ≥7).

Lower atovaquone/proguanil concentrations in patients taking efavirenz, lopinavir/ritonavir or atazanavir/ritonavir (Article)

2010-05-01T00:00:00Z

HIV-infected travellers frequently use atovaquone/proguanil as malaria prophylaxis. We compared atovaquone/proguanil pharmacokinetics between healthy volunteers and HIV-infected patients taking efavirenz, lopinavir/ritonavir or atazanavir/ritonavir. The geometric mean ratio (95% confidence interval) area under the curve (AUC)0→t for atovaquone relative to the healthy volunteers was 0.25 (0.16-0.38), 0.26 (0.17-0.41) and 0.54 (0.35-0.83) for patients on efavirenz, lopinavir/ritonavir and atazanavir/ritonavir, respectively. Proguanil plasma concentrations were also significantly lower (38-43%). Physicians should be alert for atovaquone/proguanil prophylaxis failures in patients taking efavirenz, lopinavir/ritonavir or atazanavir/ritonavir.

Polymorphisms in genes involved in vincristine pharmacokinetics or pharmacodynamics are not related to impaired motor performance in children with leukemia (Article)

2010-02-01T00:00:00Z

Introduction: Impaired motor performance in children who completed treatment for acute lymphoblastic leukemia (ALL) may be related to polymorphisms of the metabolising gene CYP3A5 or vincristine toxicity related genes MDR-1 and MAPT. Methods: Motor performance was measured with the Movement Assessment Battery for Children (movement-ABC). DNA, from mononuclear blood cells was genotyped for CYP3A5, MDR-1 and MAPT polymorphisms. Results: Motor performance was not significantly affected by CYP3A5 *3/*3 and CYP3A5*1*3 genotypes, MDR-1 polymorphisms or MAPT haplotype. Conclusion: Our data did not show that CYP3A5, MDR-1 or MAPT polymorphisms are linked to impaired motor performance in children after treatment for ALL.

CYP2D6 4, CYP3A5 3 and ABCB1 3435T polymorphisms and drug-related falls in elderly people (Article)

2010-02-01T00:00:00Z

Objective The objective of this study is to investigate the association between CYP2D64, CYP3A53 and ABCB1 3435T polymorphisms and drug-related falls. Method Multivariate logistic regression was performed in an existing database in order to study the association between falls history and CYP2D64, CYP3A53, ABCB1 3435T polymorphisms in patients using fall-risk-increasing CYP2D6, CYP3A5 and P-glycoprotein (gene product of ABCB1) substrates. Results No statistically significant increased fall risk was found in 'poor metabolizers' compared to 'extensive' and 'intermediate metabolizers' using fall-risk-increasing CYP2D6 substrates (Odds ratio (OR) = 2.2; 95% confidence interval (CI) 0.2-25.0), CYP3A5 substrates (OR = 0.9; 95% CI 0.2-3.3) and P-glycoprotein substrates (OR = 2.1; 95% CI 0.2-17.2). Conclusion The hypothesis that 'poor metabolizers' have an increased fall risk was not confirmed. A larger study population is needed to confirm the potential association that was seen between CYP2D64 and ABCB1 3435T polymorphisms and drug-related falls.

A comparison of the acid-inhibitory effects of esomeprazole and pantoprazole in relation to pharmacokinetics and CYP2C19 polymorphism (Article)

2010-01-01T00:00:00Z

Background: Esomeprazole and pantoprazole are metabolized in the liver and the polymorphic CYP2C19 enzyme is involved in that process. This genetic polymorphism determines fast (70% of Caucasians), intermediate (25-30% of Caucasians) and slow (2-5% of Caucasians) metabolism of PPIs. Aim To compare the acid-inhibitory effects of esomeprazole 40 mg and pantoprazole 40 mg at 4, 24 and 120 h after oral administration in relation to CYP2C19 genotype and pharmacokinetics. Methods CYP2C19*2, *3, *4, *5 and *17 genotypes were determined in healthy Helicobacter pylori-negative Caucasian subjects. 7 wt/wt, 7 wt/*2, 2 wt/*17, 2 *2/*17 and 1 *2/*2 were included in a randomized investigator-blinded cross-over study with esomeprazole 40 mg and pantoprazole 40 mg. Intragastric 24-h pH-monitoring was performed on days 0, 1 and 5 of oral dosing. Results A total of 19 subjects (mean age 24 years, 7 male) completed the study. At day 1 and 5, acid-inhibition with esomeprazole was significantly greater and faster than with pantoprazole. Differences in acid-inhibition and pharmacokinetics between wt/wt and wt/*2 genotype were significant for pantoprazole at day 1 and 5. Conclusions Esomeprazole provides acid-inhibition faster than and superior to pantoprazole after single and repeated administration. The acid-inhibitory effect and the kinetics of pantoprazole are influenced by CYP2C19 genotype.

Influence of genetic variation in CYP3A4 and ABCB1 on dose decrease or switching during simvastatin and atorvastatin therapy (Article)

2010-01-01T00:00:00Z

Purpose: Simvastatin and atorvastatin are metabolized by the CYP3A4 enzyme and transported by the ABCB1 transporter. We studied whether the polymorphism CYP3A4*1B and the polymorphisms C1236T, G2677A/T and C3435T in the ABCB1 gene were associated with a decrease of the prescribed dose or a switch to another cholesterol lowering drug during simvastatin and atorvastatin therapy. These events may indicate that statin plasma levels were too high and resulted in an adverse drug reaction or a too strong reduction in cholesterol level. Methods: We identified 1239 incident simvastatin and atorvastatin users in the Rotterdam Study, a population-based cohort study. Associations between the polymorphisms in the CYP3A4 and ABCB1 gene and the time to a decrease in dose or a switch to another cholesterol lowering drug were studied using Cox proportional hazards. Results: Simvastatin and atorvastatin users with the CYP3A4*1B variant G allele had a lower risk (HR 0.46; 95%CI 0.24-0.90) for these events than users with the wild-type AA genotype. No significant associations were found for the ABCB1 polymorphisms. The association with the CYP3A4*1B polymorphism was found in women (HR 0.33; 95%CI 0.12-0.89) and was non-significant in men (HR 0.69 95%CI 0.28-1.70). This association was stronger in patients with the ABCB1 3435T variant allele versus the G allele. Conclusion: In simvastatin and atorvastatin users, the CYP3A4*1B G allele is associated with a lower risk of elevated statin plasma levels, particularly in women and in users with the ABCB1 3435T variant allele. Copyright

Interaction between polymorphisms in the OCT1 and MATE1 transporter and metformin response (Article)

2010-01-01T00:00:00Z

OBJECTIVE: Metformin is transported into the hepatocyte by organic cation transporter 1 (OCT1) and out of the hepatocyte by multidrug and toxin extrusion 1 (MATE1). Recently, we discovered that polymorphisms rs622342 A>C in the SLC22A1 gene, coding for OCT1, and rs2289669 G>A in the SLC47A1 gene, coding for MATE1, are associated with the degree of glucose lowering by metformin. In this study, we assessed whether there exists an interaction between these two polymorphisms. METHODS: We identified all incident metformin users in the Rotterdam Study, a population-based cohort study. Multiplicative interaction between the polymorphisms and change in HbA1c levels was analyzed in 98 incident metformin users. RESULTS: In incident metformin users with the OCT1 rs622342 AA genotype, genetic variation at the MATE1 rs2289669 polymorphism was not associated with change in HbA1c levels [-0.10; 95% confidence interval (CI):-0.35 to 0.14; P=0.39]. In users with the OCT1 rs622342 AC genotype, there was a tendency between rs2289669 polymorphisms and change in HbA1c (-0.31; 95% CI:-0.65 to 0.03; P=0.070) and in users with the OCT1 rs622342 CC genotype there was a significant association with change in HbA1c levels (-0.68; 95% CI:-1.06 to-0.30; P=0.005). The multiplicative interaction between these two genotypes was statistically significant (-0.52; 95% CI:-0.94 to-0.11; P=0.015). CONCLUSION: The effect of the MATE1 rs2289669 polymorphism on the glucose lowering effect of metformin is larger in incident users with the OCT1 rs622342 CC genotype than in incident users with the AA genotype. The effect in incident users with the OCT1 rs622342 AC genotype is in between.

Common genetic variation in the ABCB1 gene is associated with the cholesterol-lowering effect of simvastatin in males (Article)

2009-12-02T00:00:00Z

Aims: The cholesterol-lowering drug simvastatin is a substrate for P-glycoprotein (P-gp). P-gp, encoded by ABCB1, is an efflux transporter and genetic variation in ABCB1 is associated with drug levels and response. We examined the Rotterdam Study, which is a population-based cohort study of people aged 55 years and older, to see whether the C1236T, G2677T/A and C3435T polymorphisms and haplotypes in the ABCB1 gene are associated with the total cholesterol and low-density lipoprotein cholesterol-lowering effect of simvastatin. Materials & methods: We identified 85 incident simvastatin users, for whom a cholesterol measurement both before and after the start of simvastatin therapy was available. Associations between the ABCB1 gene variants and reductions in cholesterol levels were analyzed. In our ana lysis we stratified for gender, because the level of P-gp expression in the liver is higher in men than in women. Results: The three ABCB1 polymorphisms were associated with total cholesterol reduction in the whole population. In men, both the 1236/2677/3435 TTT haplotype and the CGT haplotype were associated with larger reductions in total cholesterol (TTT: -0.40 mmol/l, 95% CI: -0.63 to -0.17; CGT: -0.44 mmol/l, 95% CI: -0.77 to -0.11) and low-density lipoprotein cholesterol levels (TTT: -0.51 mmol/l, 95% CI: -0.81 to -0.22; CGT: -0.53 mmol/l, 95% CI: -0.92 to -0.15) than the reference CGC haplotype. In women, genetic variation in the ABCB1 gene was not associated with total and low-density lipoprotein cholesterol levels. Conclusion: Male simvastatin users with the ABCB1 1236/2677/3435 TTT and CGT haplotype have larger reductions in total cholesterol and low-density lipoprotein cholesterol compared with the wild-type CGC haplotype. For women, no associations were found.

Considerations for the development of a reference method for sequencing of haploid DNA -an opinion paper on behalf of the IFCC committee on molecular diagnostics (Article)

2009-12-01T00:00:00Z

Following the completion of sequencing of the human genome, there has been a very rapid increase in the development of new molecular diagnostic tests. However, the numerous genetic tests and genetic testing technologies offered do not always satisfy essential quality criteria required to ensure confidence in the results that are produced. This is of particular importance for genetic tests since many patients may be tested for a particular genetic defect only once in their lifetime. Thus, there is a pressing need for comprehensive guidelines for the validation of molecular diagnostic tests and procedures, including DNA sequencing, the latter being a fundamental aspect of the development and validation of most genetic tests. To that end, the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) Committee for Molecular Diagnostics has prepared the following paper that describes a possible approach to the development of a reference method for sequencing of haploid DNA. We discuss various aspects which should be considered before, during and after applying the sequencing procedure, in order to achieve results with a known level of confidence, including robustness and assessments of quality.

The CYP2D6 4 polymorphism affects breast cancer survival in tamoxifen users (Article)

2009-11-01T00:00:00Z

Cytochrome P450 2D6 (CYP2D6) plays an important role in the formation of endoxifen, the active metabolite of tamoxifen. In this study the association between the most prevalent CYP2D6 null-allele in Caucasians (CYP2D64) and breast cancer mortality was examined among all incident users of tamoxifen in a population-based cohort study. Breast cancer mortality was significantly increased in patients with the 4/4 genotype (HR = 4.1, CI 95% 1.1-15.9, P = 0.041) compared to wild type patients. The breast cancer mortality increased with a hazard ratio of 2.0 (CI 95% 1.1-3.4, P = 0.015) with each additional variant allele. No increased risk of all-cause mortality or all-cancer mortality was found in tamoxifen users carrying a CYP2D64 allele. The risk of breast cancer mortality is increased in tamoxifen users with decreased CYP2D6 activity, consistent with the model in which endoxifen formation is dependent on CYP2D6 activity.

Maternal medication use, carriership of the ABCB1 3435C > T polymorphism and the risk of a child with cleft lip with or without cleft palate (Article)

2009-10-01T00:00:00Z

Gene-environment interactions in the periconceptional period play an increasing role in the pathogenesis of birth defects, including cleft lip and/or cleft palate (CL/P). The P-glycoprotein, encoded by the ABCB1 gene, is suggested to protect the developing embryo from medication and other xenobiotic exposures. Furthermore, maternal medication use during early pregnancy is a significant risk factor for CL/P offspring. Therefore, the aim of this study is to investigate the association between the maternal and child's functional ABCB1 3435C > T polymorphism, periconceptional medication exposure, and the risk of a child with CL/P. A case-control study was performed among 175 mothers and 98 of their children with CL/P and 83 control mothers and their 65 children. Information on medication and folic acid use was collected. Mothers carrying the 3435TT genotype and using medication showed a 6.2-fold (95% CI = 1.6-24.2) increased risk of having a child with CL/P compared to mothers carrying the 3435CC genotype and not using medication. Periconceptional folic acid use reduced this risk by approximately 30% (OR = 3.9, 95% CI = 0.9-18.0). Mothers carrying the 3435TT genotype, using medication and not taking folic acid showed the highest risk estimate (OR = 19.2, 95% CI = 1.0-369.2). These data suggest that mothers who carry the ABCB1 3435C > T polymorphism are at significantly increased risk for having offspring with CL/P, especially mothers using medication in the periconceptional period.

A genome-wide association study of acenocoumarol maintenance dosage. (Article)

2009-10-01T00:00:00Z

Several genome-wide association studies have been performed on warfarin. For acenocoumarol, the most frequently used coumarin in many countries worldwide, pharmacodynamic influences are expected to be comparable. Pharmacokinetics however might differ. We aimed to confirm known or identify new genetic variants contributing to interindividual variation on stabilized acenocoumarol dosage by a GWAS. The index population consisted of 1451 Caucasian subjects from the Rotterdam study and results were replicated in 287 subjects from the Rotterdam study extended cohort. Both cohorts were genotyped on the Illumina 550K Human Map SNP array. From polymorphisms tested for association with acenocoumarol dosage, 35 single nucleotide polymorphisms (SNPs) on chromosome 16 and 18 SNPs on chromosome 10 reached genome-wide significance. The SNP with the lowest P-value was rs10871454 on chromosome 16 linked to SNPs within the vitamin K epoxide reductase complex subunit 1 (VKORC1) (P = 2.0 x 10(-123)). The lowest P-value on chromosome 10 was obtained by rs4086116 within cytochrome P450 2C9 (CYP2C9) (P = 3.3 x 10(-24)). After adjustment for these SNPs, the rs2108622 polymorphism within cytochrome P450 4F2 (CYP4F2) gene on chromosome 19 reached genome-wide significance (P = 2.0 x 10(-8)). On chromosome 10, we further identified genetic variation in the cytochrome P450 2C18 (CYP2C18) gene contributing to variance of acenocoumarol dosage. Thus we confirmed earlier findings that acenocoumarol dosage mainly depends on polymorphisms in the VKORC1 and CYP2C9 genes. Besides age, gender, body mass index and target INR, one polymorphism within each of the VKORC1, CYP2C9, CYP4F2 and CYP2C18 genes could explain 48.8% of acenocoumarol dosage variation.

UGT1A9 -275T>A/-2152C>T Polymorphisms Correlate With Low MPA Exposure and Acute Rejection in MMF/Tacrolimus-Treated Kidney Transplant Patients (Article)

2009-09-01T00:00:00Z

Mycophenolate mofetil (MMF) is an immunosuppressive drug commonly used in the context of kidney transplantation. Exposure to the active metabolite mycophenolic acid (MPA) is associated with risk of allograft rejection. MPA pharmacokinetics varies between individuals, the potential cause being the presence of genetic polymorphisms in key enzymes. We genotyped 338 kidney transplant patients for UGT1A8, UGT1A9, UGT2B7, and MRP2 polymorphisms and recorded MPA exposure and biopsy-proven acute rejections (BPARs) during a 1-year follow-up. Tacrolimus-treated patients who were UGT1A9 -275T>A and/or -2152C>T carriers displayed a 20% lower MPA area under the concentration-time curve from 0 to 12 h (AUC0-12) (P = 0.012). UGT1A9*3 carriers displayed a 49% higher MPA AUC0-12 when treated with tacrolimus and a 54% higher MPA AUC0-12 when treated with cyclosporine (P < 0.005). Cyclosporine-treated UGT1A8*2/*2 (518GG) patients had an 18% higher MPA AUC0-12 compared with noncarriers. Carrying the UGT1A9 -275T>A and/or -2152C>T polymorphism significantly predicted acute rejection in fixed-dose (FD) MMF-treated patients receiving tacrolimus (odds ratio 13.3, 95% confidence interval 1.1-162.3; P < 0.05). UGT1A9 -275T>A and/or -2152C>T genotyping may identify patients at risk of MPA underexposure and acute rejection when receiving treatment with MMF and tacrolimus.Clinical Pharmacology & Therapeutics (2009); advance online publication 03 June 2009. doi:10.1038/clpt.2009.83.

Interpatient variability in IMPDH activity in MMF-treated renal transplant patients is correlated with IMPDH type II 3757T>C polymorphism (Article)

2009-08-01T00:00:00Z

OBJECTIVES: The active metabolite of mycophenolate mofetil (MMF), mycophenolic acid, inhibits the activity of the target enzyme inosine monophosphate dehydrogenase (IMPDH). The aim of this study was to correlate eight different single nucleotide polymorphisms of the IMPDH type II gene to the activity of the IMPDH enzyme to explain between-patient differences in IMPDH activity. METHODS AND RESULTS: In a prospective study, we measured IMPDH activity, mycophenolic acid plasma concentrations, and eight polymorphisms of IMPDH type II in de novo kidney transplant recipients, 6 days posttransplantation while on MMF treatment. Polymorphisms in the IMPDH type II gene were only observed for the IMPDH type II 3757T>C (rs11706052) single nucleotide polymorphism. Ten of 101 patients (10%) were heterozygous and two of 101 patients (2%) homozygous for IMPDH type II 3757T>C. The allele frequency was 6.9%. The IMPDH activity over 12h (AUCact) was 49% higher for patients with an IMPDH type II 3757C variant [n=12 vs. n=68; 336 (95% confidence interval: 216-521) vs. 227 (95% confidence interval: 198-260)hμmol/s/mol adenosine monophosphate; P=0.04]. The IMPDH activity measured before transplantation (Actpre-Tx) was not significantly different between IMPDH type II 3757TT wild-type and variant carrier patients (P=0.99). CONCLUSION: We report that the IMPDH type II 3757T>C polymorphism is associated with an increased IMPDH activity in MMF-treated renal transplant patients. This polymorphism explains 8.0% of the interpatient variability in IMPDH activity.

Variation in the CYP2D6 gene is associated with a lower serum sodium concentration in patients on antidepressants (Article)

2009-08-01T00:00:00Z

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Several antidepressants are metabolized by the polymorphic enzyme cytochrome P450 2D6 (CYP2D6). • The variant allele CYP2D6*4 is the main polymorphism resulting in decreased enzyme activity in Caucasians. • Decreased CYP2D6 enzyme activity potentially leads to higher plasma concentrations of antidepressants. • Consequently, patients carrying the *4 allele are more likely to suffer from adverse drug reactions such as hyponatraemia. WHAT THIS STUDY ADDS • The association between CYP2D6 genotype and serum sodium concentration in users of antidepressants has not been examined thoroughly, and most studies suffer from small numbers of poor metabolizers (PMs) of CYP2D6. • This study shows that serum sodium concentrations in users of tricyclic antidepressive drugs are lower in CYP2D6 PMs than in extensive metabolizers. AIM To study the effect of the CYP2D6*4 polymorphism on serum sodium concentration in users of antidepressants [selective serotonin reuptake inhibitors and tricyclic antidepressants (TCAs)]. METHODS In this population-based cohort study, all subjects in the Rotterdam Study were included who used an antidepressant at baseline and from whom a blood sample was available in which CYP2D6 genotype and serum sodium concentration could be determined (n = 76). Multivariate linear regression was used to study the association between CYP2D6*4 and serum sodium concentration. RESULTS CYP2D6 poor metabolizers (PMs) (*4/*4) had a significantly lower mean serum sodium concentration in comparison with CYP2D6 extensive metabolizers (EMs) (*1/*1) [difference -3.9 mmol l-1; 95% confidence interval (CI) -0.86, -7.03; P = 0.013]. In CYP2D6*4 heterozygotes (*1/*4) serum sodium concentration was 1.7 mmol l-1(95% CI -3.48, 0.18) lower compared with CYP2D6 EMs, but this difference was not statistically significant (P = 0.077). CONCLUSIONS The serum sodium concentration in PMs was lower in users of an antidepressant, especially in TCA users. Therefore CYP2D6 PMs might be at increased risk of developing symptoms of hyponatraemia.

Association between the CYP2D6*4 polymorphism and depression or anxiety in the elderly (Article)

2009-06-16T00:00:00Z

Introduction: 5-methoxytryptamine (5-MT), a precursor of serotonin, is considered to be an endogeous substrate of cytochrome P450 2D6 (CYP2D6). Homozygous carriers of the variant allele CYP2D6*4 lack CYP2D6 emzyme activity. Relative to extensive metabolizers, these poor metabolizers may have lower baseline serotonin concentrations in various brain regions, and may be more prone to depression or anxity. Aim: To test whether the CYP2D6*4/*4 genotype is associated with a predisposition to depression or anxiety disorders in the elderly. Materials & methods: We conducted a cross-sectional study within the Rotterdam Study, a population-based cohort study, among persons aged 55 years or older, who were screened for depression and anxiety disorder at two consecutive examination rounds. Logistic regression was used to analyze the association between the CYP2D6*4 polymorhism and the risk of depression or anxiety disorders. Results: The risk of major depression in CYP2D*64/*4 was not significantly different from extensive metabolizers (OR = 0.85; 95% Cl: 0.36-2.00; p = 0.72). Neither did we find an association between CYP2D6 genotype and minor depression (OR = 1.56; 95% Cl: 0.69-3.52; p = 0.28). No increased risk of anxiety disorders was found (OR = 1.19; 95% Cl: 0.68-2.09; p = 0.55). Conclusion: Variation in the CYP2D6 gene is not related to a predisposition or anxiety disorders in the elderly.

Genotypes associated with reduced activity of VKORC1 and CYP2C9 and their modification of acenocoumarol anticoagulation during the initial treatment period (Article)

2009-04-01T00:00:00Z

The objective of this study was to investigate the influence of genotypes associated with reduced activity of vitamin K epoxide reductase complex subunit 1 (VKORC1) and cytochrome P450 2C9 (CYP2C9) on anticoagulation with acenocoumarol during the first 6 weeks of treatment. In 1,525 patients from the Rotterdam Study who were started on anticoagulation therapy with acenocoumarol, the presence of VKORC1 1173C>T and CYP2C9*2 and *3 allele variants was determined. The first international normalized ratio (INR) after initial standard dose, risk of overanticoagulation, and mean dosage at the end of the initiation period were compared between genotypes. The initial standard dosage significantly increased the risk of severe overanticoagulation by 85% for each additional VKORC1 T-allele present. At the end of the initiation period, each VKORC1 T-allele present was shown to decrease the required acenocoumarol dosage by 5.1 mg/week, while each CYP2C9 variant allele present reduced the required dosage by 1.8 mg/week. Our conclusion was that an initial standard dosing regimen with acenocoumarol increases the risk of severe overanticoagulation in patients with variant alleles of the VKORC1 and CYP2C9 genes.

Efavirenz dose reduction to 200 mg once daily in a patient treated with rifampicin (Article)

2009-03-27T00:00:00Z

Genetic variation in the multidrug and toxin extrusion 1 transporter protein influences the glucose-lowering effect of metformin in patients with diabetes: A preliminary study (Article)

2009-03-01T00:00:00Z

OBJECTIVE-Metformin, an oral glucose-lowering drug, is taken up in hepatocytes by the organic cation transporter (OCT) 1 and in renal epithelium by OCT2. In these cells, the multidrug and toxin extrusion (MATE) 1 protein, encoded by the SLC47A1 gene, is responsible for the excretion of metformin into the bile and urine, respectively. We studied the effect of single nucleotide polymorphisms (SNPs) in the SLC47A1 gene on the A1C-lowering effect of metformin. RESEARCH DESIGN AND METHODS-We identified all incident metformin users in the Rotterdam Study, a population- based cohort study. Associations between 12 tagging SNPs in the SLC47A1 gene and change in A1C level were analyzed. RESULTS-One hundred and sixteen incident metformin users were included in the study sample. The rs2289669 G> A SNP was significantly associated with metformin response. For the other SNPs, no associations were found. For each minor A allele at rs2289669, the A1C reduction was 0.30% (95% CI -0.51 to -0.10; P = 0.005) larger. After Bonferroni correction for multiple testing, the P value was 0.045. CONCLUSIONS-The rs2289669 G>A SNP is associated with a reduction in A1C level, consistent with a reduction in MATE1 transporter activity. These results suggest that the transporter MATE1, encoded by SLC47A1, may have an important role in the pharmacokinetics of metformin, although replication is necessary.

Pharmacogenetic pathway analysis of docetaxel elimination (Article)

2009-02-01T00:00:00Z

The purpose of this study was to evaluate the affinity of docetaxel for 14 transporter proteins and assess the functional significance of 17 variants in five genes involved in drug elimination. Among the transfected models investigated, OATP1B3 (SLCO1B3) was identified as the most efficient influx transporter for docetaxel. None of the observed genotypes (SLCO1B3, ABCB1, and ABCC2) was related with docetaxel clearance in 92 white patients (P > 0.17). However, the simultaneous presence of the CYP3A4*1B and CYP3A5*1A alleles was associated with a 64% increase in docetaxel clearance (P < 0.0015), independent of both sex and CYP3A activity (as determined using the erythromycin breath test). This haplotype was also associated with increased midazolam clearance in another population (P < 0.0198). An analysis of the CYP3A locus among CEPH-HapMap samples revealed that CYP3A4*1B is present exclusively among a subset of CYP3A5 expressors. Therefore, future studies should first stratify the population on the basis of CYP3A5 genotype and then compare CYP3A activity between individuals with and without the CYP3A4*1B allele.

No modification of the beneficial effect of NSAIDs on colorectal cancer by CYP2C9 genotype (Article)

2009-01-01T00:00:00Z

Background: CYP2C9 enzymes are involved in non-steroidal anti-inflammatory drug (NSAID) metabolism. Therefore, we investigated whether CYP2C9*2 and *3 variant alleles, encoding for enzymes with lower activity, increased the protective effect of NSAIDs on colorectal cancer. Methods: Individual and combined associations of NSAIDs and CYP2C9*2 and 3 variant alleles with colorectal cancer were studied in 7757 Caucasian individuals of The Rotterdam Study, a population-based prospective cohort since 1990. Additive and multiplicative effect modification models were used to examine drug-gene interactions. Results: There were 212 incident cases of colorectal cancer during follow-up. A reduced risk of colorectal cancer was observed in individuals who used NSAIDs for more than a year (HR 0.45; 95% CI 0.28 to 0.71), and in carriers of an CYP2C9 variant allele associated with lower enzymatic activity (HR 0.67; 95% CI 0.47 to 0.96). The combination of both determinants was associated with a further risk reduction but without synergy. Conclusion: Both NSAID use and CYP2C9*2 and/or *3 carriage are associated with a reduced risk of colorectal cancer. However, no interaction between the determinants was found, which might indicate independent pathophysiological mechanisms.

Genetic variation in the CYP2D6 gene is associated with a lower heart rate and blood pressure in β-blocker users (Article)

2009-01-01T00:00:00Z

Several β-blockers are metabolized by the polymorphic enzyme cytochrome P450 2D6 (CYP2D6). CYP2D6*4 is the main polymorphism leading to decreased enzyme activity. The clinical significance of impaired elimination of β-blockers is controversial, and most studies suffer from inclusion of small numbers of poor metabolizers (PMs) of CYP2D6. In this study, the association between CYP2D6*4 and blood pressure or heart rate was examined in 1,533 users of β-blockers in the Rotterdam Study, a population-based cohort study. In CYP2D6 *4/*4 PMs, the adjusted heart rate in metoprolol users was 8.5 beats/min lower compared with *1/*1 extensive metabolizers (EMs) (P < 0.001), leading to an increased risk of bradycardia in PMs (odds ratio = 3.86; 95% confidence interval 1.68-8.86; P = 0.0014). The diastolic blood pressure in PMs was 5.4 mm Hg lower in users of β-blockers metabolized by CYP2D6 (P = 0.017) and 4.8 mm Hg lower in metoprolol users (P = 0.045) compared with EMs. PMs are at increased risk of bradycardia.

Clinical impact of new prostate-specific antigen WHO standardization on biopsy rates and cancer detection (Article)

2008-12-01T00:00:00Z

BACKGROUND: Clinicians may be unaware that replacement of the historical total prostate-specific antigen (tPSA) standard with the WHO 96/670 international standard leads to difficulties in interpreting tPSA results. Our aim was to investigate the relationship between the Hybritech and WHO calibrations of the Beckman Coulter tPSA assay, and to assess the impact on prostate cancer (PCa) detection. METHODS: tPSA concentrations were measured in 106 serum samples with both Hybritech and WHO calibrations. The established relationships were used for an in silico experiment with a cohort of 5865 men. Differences in prostate biopsy rates, PCa detection, and characteristics of missed cancers were calculated at biopsy thresholds of 3.0 and 4.0 μg/L. RESULTS: A linear relationship was observed between the 2 calibrations, with a 20.3% decrease in tPSA values with the WHO standard compared with the Hybritech calibration. Applying the WHO calibration to the cohort of 5865 men yielded a 20% or 19% decrease in prostate biopsies and a 19% or 20% decrease in detected cancers compared with the Hybritech calibration, at a cutoff for biopsy of 3.0 or 4.0 μg/L, respectively. The decrease in detected cancers declined to 9% or 11% if an abnormal result in a digital rectal examination or a transrectal ultrasound evaluation was used as trigger for prostate biopsy (cutoff of 3.0 or 4.0 μg/L, respectively). CONCLUSIONS: Application of the WHO standard for tPSA assays with commonly used tPSA thresholds leads to a significant decrease in PCa detection. Careful assessment of the relationship between the WHO standard and the thresholds used for prostate biopsy is hence necessary.

A drug transporter for all ages? ABCB1 and the developmental pharmacogenetics of cyclosporine (Article)

2008-09-01T00:00:00Z

The clinical use of the immunosuppressive agent cyclosporine is complicated by its toxicity, narrow therapeutic window and highly variable pharmacokinetics between individuals. In adults, genetic polymorphisms in the genes encoding the cyclosporine-metabolizing enzymes CYP3A4 and CYP3A5, as well as the ABCB1 gene, which encodes the efflux-pump P-glycoprotein, seem to have a limited effect, if any, on cyclosporine pharmacokinetics. However, the authors have now reported for the first time an association between cyclosporine oral bioavailability and the ABCB1 c.1236C>T and c.2677G>T polymorphisms, as well as the related haplotype c.1199G-c.1236C-c.2677G-c.3435C, in children with end-stage renal disease older than 8 years of age. Carriers of the variant alleles had a cyclosporine oral bioavailability that was around 1.5-times higher compared with noncarriers. This association was not observed in children younger than 8 years of age. In addition, no relation between cyclosporine disposition and genetic variation in the CYP3A4, CYP3A5, ABCC2, SLCO1B1 and NR1I2 genes was observed. These data suggest that the effect of ABCB1 polymorphisms on cyclosporine pharmacokinetics is related to age, and thus developmental stage. Although further study is necessary to establish the predictive value of ABCB1 genotyping for individualization of cyclosporine therapy in children older than 8 years, an important step towards further personalized immunosuppressive drug therapy has been made.

Postmenstrual age and CYP2D6 polymorphisms determine tramadol O-demethylation in critically ill neonates and infants (Article)

2008-06-01T00:00:00Z

To document determinants of O-demethylation in critically ill (pre)term neonates and infants, tramadol (M) and O-demethyl tramadol (M1) concentrations were quantified in eighty-six 24 h urine collections and 168 plasma samples. A significant correlation of urine log M/M1 (0.98, SD 0.66) and plasma log M/M1 (0.78, SD 0.45) with postmenstrual age (PMA) (r = -0.69 and -0.65) was observed. One-way analysis of variance documented a significant decrease in urine log and plasma log M/M1 with increasing CYP2D6 activity score (F value 11.6 and 22.55). PMA and CYP2D6 activity score determined the urine and plasma log M/M1 (R 0.59 and 0.64) in a forward multiple regression model. We therefore conclude that PMA and CYP2D6 polymorphisms determined O-demethylation activity in (pre)term neonates and young infants, illustrating the impact of pharmacogenetics on drug metabolism in neonates although a relevant part of the interindividual varaibility remained unexplained. Besides compound-specific relevance, CYP2D6 iso-enzyme specific data on in vivo ontogeny of O-demethylation can contribute to safer and more effective administration of drugs metabolized by the same route in this population. Copyright

Association of graded allele-specific changes in CYP2D6 function with imipramine dose requirement in a large group of depressed patients (Article)

2008-06-01T00:00:00Z

The inactivation and clearance of the tricyclic antidepressant imipramine is dependent on CYP2D6 activity. First, CYP2C19 converts imipramine into the active metabolite desipramine, which is then inactivated by CYP2D6. This retrospective single center study aimed to prove whether CYP2C19 and ample CYP2D6 genotyping (taking into consideration four null alleles and three decreased-activity alleles) could be used to predict imipramine and desipramine plasma concentrations in depressed patients, and whether genotype-based drug dose recommendations might assist in the early management of imipramine pharmacotherapy. In 181 subjects with major depressive disorder, drug doses were recorded, imipramine and desipramine plasma concentrations were monitored and CYP2C19 (*2) and CYP2D6 genotype (*3, *4, *5, *6, *9, *10, *41 and gene duplication) were obtained, yielding graded allele-specific CYP2D6 patient groups. Desipramine and imipramine+desipramine plasma concentration per drug dose unit, imipramine dose at steady state, and imipramine dose requirement significantly depended on CYP2D6 genotype (Kruskal-Wallis test, P<0.0001). Mean (±s.d.) drug dose requirements were 131 (±109), 155 (±70), 217 (±95), 245 (±125), 326 (±213), and 509 (±292) mg imipramine/day in carriers of 0, 0.5, 1, 1.5, 2, and >2 active CYP2D6 genes, respectively. Our protocol for CYP2D6 genotyping will thus importantly aid in the prediction of imipramine metabolism, allowing for the use of an adjusted starting dose and faster achievement of predefined imipramine+desipramine plasma levels in all genetic patient subgroups. Therefore, therapeutic efficacy and efficiency may be improved, the number of adverse drug reactions decreased, and hospital stay reduced.

CYP450 pharmacogenetics for personalizing cancer therapy (Article)

2008-06-01T00:00:00Z

Today's drug therapy regimens rely on the anticipated relation between drug dose, acquired plasma level and desired effect. However, the capacity of individual patients to absorb and metabolise drugs may differ significantly, part of which is due to genetic factors. These genetic factors can be used to predict the drug metabolizing potential of patients before starting therapy. A major challenge is to identify the genetic polymorphisms which are relevant for a particular therapy and to determine the clinical consequences with respect to dosing, or choice of drug, based on the outcome of pharmacogenetic analyses. For the cytochrome P450 system, which catalyzes oxidative reactions, many new genetic polymorphisms have been identified in the last years. In this review, the current knowledge of cytochrome P450 polymorphisms with respect to cancer treatment is described, highlighting the potential of reaching considerable benefit from personalized therapy, either by improving efficacy or reducing the toxicity of current treatment regimens. This review specifically addresses the knowledge today on cytochrome P450 pharmacogenetics for tamoxifen, docetaxel, paclitaxel, cyclophosphamide, ifosfamide, imatinib, gefitinib, irinotecan, etoposide, teniposide, thalidomide and vincristine therapies, discussing its current potential for individualized therapy based on cytochrome P450 genetic polymorphisms.

Effect of CYP2C192 and 17 mutations on pharmacodynamics and kinetics of proton pump inhibitors in Caucasians (Article)

2008-05-01T00:00:00Z

AIMS: To investigate the impact of CYP2C19 mutations *2-*6 and *17 on acid-inhibition and pharmacokinetics of lansoprazole (L15), omeprazole (O10, O20) and pantoprazole (P40) in Caucasians. METHODS: CYP2C19 genotyping for *2-*6 and *17 mutations was assessed in subjects who were H. pylori negative in two randomized crossover trials. The influence of CYP2C19 mutations on single and repeated administration of L15 and O10 (study A) and O20 and P40 (study B) was investigated. Pharmacokinetics and the cumulative percentage of time with intragastric pH above 4 (% > pH 4) were assessed on day 1 and 6. RESULTS: For study A CYP2C19 genotyping found five *1/*1, four *1/*2, one *1/*17 and one *2/*17. For study B the results were six *1/*1, two *1/*2, six *1/*17, one *2/*2 and one *2/*17. For all PPIs AUC was highest in *2/*2 and lowest in *1/*17. On day 1, all PPIs significantly increased percentage >pH 4 compared with baseline. *1/*1 genotype showed no significant acid-inhibition after L15, O10 and O20. *1/*17 genotype showed no significant acid-inhibition after O20 and P40. *1/*2 genotype showed significant acid-inhibition after L15 and O10. On day 6, all four PPIs showed significantly increased acid-inhibition. *1/*1 and *1/*17 showed a significantly increased percentage > pH 4 after treatment with O20 and P40. However, in *1/*1 subjects percentage > pH 4 was not significantly increased after L15 and O10. *1/*2 genotype showed a significant acid-inhibitory effect after repeated dosing with L15 and O10. CONCLUSIONS: Caucasian subjects with *1/*1 and *1/*17 genotype need stronger acid-suppression therapy, especially during the first days of treatment or with on-demand therapy.

Covariates of tramadol disposition in the first months of life (Article)

2008-04-01T00:00:00Z

Background. Data on contributors to between-individual variability in overall tramadol clearance and O-demethyl tramadol (M1) formation in preterm neonates and young infants are limited. Methods. A population pharmacokinetic analysis of tramadol and M1 was undertaken using non-linear mixed effects model. Covariate analysis included weight, postmenstrual age (PMA), postnatal age (PNA), creatinaemia, (cardiac) surgery, cardiac defect, and cytochrome (CYP)2D6 polymorphisms, classified by CYP2D6 activity score. Results. In 57 patients (25-54 weeks PMA), 593 observations were collected. Tramadol clearance was described using a two-compartment, zero-order input, first-order elimination linear model. An additional compartment was used to characterize M1. Tramadol clearance at term age was 17.1 litre h-1(70 kg)-1(CV, 37.2%). Size (37.8%) and PMA (27.3%) contribute to this variability. M1 formation clearance (CL2M1, i.e. the contribution of M1 synthesis to M clearance) was 4.11 litre h-1(70 kg)-1(CV, 110.9%) at term age. Size and PMA were the major contributors to the variability (52.7%); the CYP2D6 activity score contributes 6.4% to this variability. Conclusions. Overall tramadol clearance estimates confirm earlier reports while CL2M1 variability is explained by size, PMA, and CYP2D6 polymorphisms. The CL2M1 is very low in preterm neonates, irrespective of the CYP2D6 polymorphism with subsequent rapid maturation. The slope of this increase depends on the CYP2D6 activity score. The current pharmacokinetic observations suggest a limited μ-opioid receptor-mediated analgesic effect of M1 in preterm neonates and a potential CYP2D6 polymorphism-dependent effect beyond term age.

Influence of the CYP2D6*4 polymorphism on dose, switching and discontinuation of antidepressants (Article)

2008-04-01T00:00:00Z

Aims: To study the effect of CYP2D6*4 on antidepressant dose, switching and discontinuation of therapy. Methods: The study consisted of all subjects in the Rotterdam Study, who received a first antidepressant prescription between April 1st 1991 and July 1st 2005 and for whom data on CYP2D6 genotype were available. Binary logistic regression was performed to study the association between CYP2D6*4 and switching to any other antidepressant or discontinuation of therapy within 45 days. The difference in mean antidepressant dose was compared between CYP2D6 genotypes using t-tests and repeated measurements analyses. Results: In users of tricyclic antidepressants (TCAs) the risk of switching to another antidepressant was significantly higher in poor metabolizers (PMs:*4/*4) compared with extensive metabolizers (EMs:*1/*1), with an adjusted OR of 5.77 (95% CI 1.59, 21.03; P = 0.01). In SSRI users there was no significant difference (OR 0.91; 95% CI 0.20, 4.15; P = 0.90). Heterozygous patients did not have an increased risk of switching in both TCA and SSRI users. The mean TCA dose was significantly lower in PMs than in EMs at the third and fourth prescription (difference 0.11 DDD, P = 0.03). In SSRI users the difference in mean dose between PMs and EMs was significant at the third prescription (0.17 DDD; P = 0.02). Conclusions: The risk of switching to another antidepressant in TCA users is higher in PMs than in EMs. The maintenance doses of antidepressants were significantly lower in PMs. However, the question whether genotyping prior to the start of antidepressant therapy contributes substantially to the optimization of pharmacotherapy, requires further study.

Vitamin K epoxide reductase complex subunit 1 (VKORC1) polymorphism and aortic calcification: The Rotterdam study (Article)

2008-04-01T00:00:00Z

OBJECTIVE - Besides effects on hemostasis, vitamin K-dependent proteins play a role in bone mineralization and arterial calcification. We investigated the association between the VKORC1 1173C>T polymorphism and calcification of the aortic far wall in a large population-based cohort. METHODS AND RESULTS - Aortic calcification was diagnosed by radiographic detection of calcified deposits in the abdominal aorta. In all cohort members for whom DNA was available, the C1173T SNP of VKORC1 (rs9934438) was determined. With multivariable logistic regression analysis the association between this polymorphism and the risk of aortic calcification was calculated, adjusted for potential confounders. The T allele frequency of the VKORC1 1173C>T polymorphism was 38.8%. 1185 (37.2%) persons were homozygous CC, 1529 (48,0%) were heterozygous CT and 473 (14.8%) were homozygous TT. Persons with at least one T-allele had a statistically significant 19% (95% CI 2 to 40%) risk increase of calcification of the aortic far wall compared to CC homozygous persons, adjusted for age and gender. CONCLUSION - The T-allele of the VKORC1 1173C>T polymorphism was associated with a significantly higher risk of aortic calcification in Whites.

CYP3A5 genotype is not associated with a higher risk of acute rejection in tacrolimus-treated renal transplant recipients (Article)

2008-04-01T00:00:00Z

OBJECTIVE: Patients expressing the tacrolimus-metabolizing enzyme, cytochrome P450 (CYP) 3A5, require more tacrolimus to reach target concentrations. We studied the influence of the CYP3A5*3 allele, which results in the absence of CYP3A5 protein, on tacrolimus dose and exposure, as well as the incidence of biopsy-proven acute rejection (BPAR) after renal transplantation. METHODS: A total of 136 patients participating in a prospective, randomized-controlled clinical trial with the primary aim of comparing the efficacy of a fixed-dose versus a concentration-controlled mycophenolate mofetil immunosuppressive regimen, were genotyped for CYP3A5*3. The patients described herein, participated in a pharmacogenetic substudy and were all treated with mycophenolate mofetil, corticosteroids and tacrolimus. Tacrolimus predose concentrations (C0) were measured on day 3 and 10, and month 1, 3, 6 and 12. RESULTS: Compared with CYP3A5*3/*3 individuals (n=110), patients carrying at least one CYP3A5*1 (wild-type) allele (CYP3A5 expressers; n=26) had a lower tacrolimus C0 on day 3 only (16.6 versus 12.3 ng/ml, respectively), whereas dose-corrected tacrolimus C0 were significantly lower in the latter group at all time points. After day 3, the overall daily tacrolimus dose was 68% higher in CYP3A5 expressers (P<0.001). The incidence of BPAR was comparable between CYP3A5 expressers and nonexpressers (8 versus 16%, respectively; P=0.36). CONCLUSION: We conclude that patients expressing CYP3A5 need more tacrolimus to reach target concentrations and have a lower tacrolimus exposure shortly after transplantation. This delay in reaching target concentrations, however, did not result in an increased incidence of early BPAR and therefore, genotyping for CYP3A5 is unlikely to improve short-term transplantation outcome.

Common ATP-binding cassette B1 variants are associated with increased digoxin serum concentration (Article)

2008-04-01T00:00:00Z

BACKGROUND AND OBJECTIVE: Digoxin is a known substrate of ATP-binding cassette B1 (ABCB1/MDR1). The results of studies on the association between ABCB1 polymorphisms and digoxin kinetics, however, remain contradictory. Almost all studies were small and involved only single dose kinetics. The goal of this study was to establish ABCB1 genotype effect on digoxin blood concentrations in a large cohort of chronic digoxin users in a general Dutch European population. METHODS: Digoxin users were identified in the Rotterdam Study, a prospective population-based cohort study of individuals aged 55 years and above. Digoxin blood levels were gathered from regional hospitals and laboratories. ABCB1 single nucleotide polymorphisms (SNPs) 1236C→T, 2677G→T/A, and 3435C→T were assessed on peripheral blood DNA using Taqman assays. We studied the association between the ABCB1 genotypes and haplotypes, and digoxin blood levels using linear regression models adjusting for potential confounders. RESULTS: Digoxin serum levels and DNA were available for 195 participants (56.4% women, mean age 79.4 years). All three ABCB1 variants were significantly associated with serum digoxin concentration (0.18-0.21 μg/l per additional T allele). The association was even stronger for the 1236-2677-3435 TTT haplotype allele [0.26 μg/l (95% CI 0.14-0.38)], but absent for other haplotypes (CGC allele considered referent), suggesting an interaction of SNPs in a causal haplotype instead of individual SNP effects. CONCLUSION: We found that the common ABCB1 1236C→T, 2677G→T, and 3435C→T variants and the associated TTT haplotype were associated with higher digoxin serum concentrations in a cohort of elderly European digoxin users in the general population.

UGT2B7 promoter variant -840G>A contributes to the variability in hepatic clearance of morphine in patients with sickle cell disease (Article)

2008-03-01T00:00:00Z

The purpose of the study was to determine if UDP-glucuronosyltransferase (UGT) 2B7 allelic variants encoding for UGT2B7, primary enzyme responsible for morphine glucuronidation contribute to the variability in the hepatic clearance of morphine in sickle cell disease (SCD). Twenty-four hour PK study of morphine and UGT2B7 variants genotyping was performed in 20 SCD patients in a steady state of health. Presence of the -840G allele (GG and GA) was associated with lower morphine metabolites/morphine AUC ratio compared with AA genotype (1.8 ± 0.5 vs. 3.0 ± 1.8 for M6G/M and 10.1 ± 2.7 vs. 15.7 ± 9.4 for M3G/M) (P = 0.03). Presence of UGT2B7 -840G allele is associated with significantly reduced glucuronidation of morphine and thus contributes to the variability in hepatic clearance of morphine in SCD.

Cytochrome P450 2C9 2 and 3 polymorphisms and the dose and effect of sulfonylurea in type II diabetes mellitus (Article)

2008-02-01T00:00:00Z

Sulfonylurea hypoglycemics are mainly metabolized by the cytochrome P450 2C9 (CYP2C9) enzyme. The CYP2C9*2 and *3 polymorphisms encode proteins with less enzymatic activity and are correlated with elevated serum levels of sulfonylurea, as demonstrated in healthy volunteers. In this study, the effect of these variants is described for patients with diabetes mellitus treated with sulfonylurea. Associations between CYP2C9 polymorphisms, prescribed doses of sulfonylurea, and change in glucose levels after the start of sulfonylurea therapy were assessed in all patients with incident diabetes mellitus starting on sulfonylurea therapy in the Rotterdam Study, a population-based cohort study of 7,983 elderly people. In CYP2C9*3 allele carriers using tolbutamide, the prescribed dose was lower compared to patients with the wild-type CYP2C9 genotype. No differences in the prescribed dose were found in tolbutamide users with the CYP2C9*1/*2 or CYP2C9*2/*2 genotype compared to wild-type patients or in patients using other sulfonylurea. In CYP2C9*3 allele carriers, the mean decrease in fasting serum glucose levels after the start of tolbutamide therapy was larger than in patients with the wild-type genotype, although not statistically significant. Patients with diabetes mellitus who are carriers of a CYP2C9*3 allele require lower doses of tolbutamide to regulate their serum glucose levels compared to patients with the wild-type genotype.

MUC1 568 A/G genotype-dependent Cancer Antigen 15-3 levels in breast cancer patients (Article)

2008-01-01T00:00:00Z

Objectives: CA 15-3 is a widely used tumor marker for breast cancer. We have investigated whether the MUC1 568 A/G polymorphism can influence CA 15-3 levels in healthy women and patients with breast tumors. Design and methods: CA 15-3 was measured in 208 healthy women, in 67 with benign disease, and in 162 women with breast cancer. All subjects were genotyped for the MUC1 568 A/G polymorphism. Results: Significant differences were observed between mean CA 15-3 levels of control subjects grouped according to the MUC1 568 genotype (mean ± SD): AA (10.3 ± 3.8), AG (15.9 ± 5.0) and GG (19.0 ± 5.6) U/mL, p < 0.0001. Similar (median) results were observed in women with benign breast disease: AA (10.2), AG (14.2) and GG (16.6) U/mL, p < 0.0001, and those with breast cancer: AA (10.4), AG (17.1) and GG (23.9) U/mL, p < 0.0001. Conclusions: The MUC1 568 A/G polymorphism strongly influences CA 15-3 levels in healthy women and women with either benign or malignant breast tumors.

Hepatotoxicity of oral and intravenous voriconazole in relation to cytochrome P450 polymorphisms (Article)

2007-11-01T00:00:00Z

Objectives: Voriconazole, like all other antifungals of the azole group, is potentially hepatotoxic. A large interpatient variability of liver enzyme elevations during oral or intravenous (iv) voriconazole administration is observed. This interpatient variability may be explained by differences in voriconazole metabolism because of cytochrome P450 polymorphisms. We examined the relationship between cytochrome P450 polymorphisms and hepatotoxicity in immunocompromised patients predominantly receiving oral formulations of voriconazole. Methods: In a single institution retrospective study of 86 immunocompromised patients receiving oral (n = 74) or iv (n = 12) voriconazole, we studied the influence of cytochrome P450 polymorphisms (CYP2C19, CYP2C9 and CYP3A5) on the maximum bilirubin and serum liver enzyme levels [alkaline phosphatase, gamma-glutamyl transpeptidase (GGT), serum aspartate aminotransferase and serum alanine aminotransferase] and their respective common toxicity criteria scores (CTC-scores). Results: Median serum bilirubin as well as the level of all other liver enzymes increased during voriconazole treatment. A decline in CTC-score was observed in zero (0%) to six (7%) patients; an increase in CTC-score was demonstrated in 36 (42%) to 54 (63%) patients. No statistically significant differences in maximum value or maximum increase of liver enzymes or CTC-score in relation to cytochrome P450 polymorphisms were observed. Only a trend towards higher maximum CTC-score of GGT for wild-type of CYP2C9 was observed (P = 0.046). Conclusions: No significant relationship between CYP2C9, CYP2C19 or CYP3A5 polymorphisms and serum liver enzyme levels was observed in patients treated with voriconazole.

Tubular and Interstitial Nephrocalcinosis (Article)

2007-09-01T00:00:00Z

Purpose: We determined whether nephrocalcinosis is common and whether its detection is influenced by renal tissue processing. Materials and Methods: Renal cortical and papillary tissue was obtained from the unaffected parts of 15 kidneys removed due to an oncological indication. The effect of tissue processing on the loss of crystals was studied in a kidney with nephrocalcinosis due to chronic pyelonephritis. Immediately frozen and formaldehyde fixed sections were analyzed by polarized light and Raman spectroscopy, and stained for calcium (Yasue) and hyaluronan. Results: Although 13 of 15 snap-frozen sections from tumor kidneys contained birefringent particles (mean ± SD 3.2 ± 2.9 particles per cm2) in the renal tubules, this was not considered nephrocalcinosis because the crystals were not attached to the epithelial lining. Interstitial nephrocalcinosis was found on Yasue stain in 3 of 15 kidneys with tumor (20%). Calcium deposits were found in the papillary interstitium only, always together with hyaluronan. Formaldehyde fixed sections from the pyelonephritis kidney contained fewer renal tubular cell associated birefringent particles than immediately frozen sections (9.4 ± 1.9 vs 41.6 ± 1.2 per cm2). Particles were composed of calcium oxalate monohydrate (Yasue and Raman). Conclusions: There are 2 distinct forms of nephrocalcinosis, including tubular nephrocalcinosis, which seems to be reserved for specific conditions such as chronic pyelonephritis, and interstitial nephrocalcinosis. The incidence of tubular calcium oxalate nephrocalcinosis could be underestimated due to the loss of crystals during tissue processing for routine histology. The crystal binding molecule hyaluronan may have a role in the 2 forms of nephrocalcinosis.

Influence of ketoconazole on the fecal and urinary disposition of docetaxel (Article)

2007-09-01T00:00:00Z

Objective: The anticancer drug docetaxel is extensively metabolized by cytochrome P450 (CYP) 3A isozymes. Furthermore, docetaxel is also a substrate for the transmembrane ATP-binding cassette efflux transporter protein ABCB1. CYP3A-inhibition significantly reduces docetaxel total systemic clearance, on average by 50%. However, data on the effect of CYP3A-inhibition on the fecal and urinary excretion of docetaxel are lacking. To further elucidate the role of CYP3A- and ABCB1-mediated elimination pathways for docetaxel we investigated the effect of the potent CYP3A-inhibitor, and also ABCB1-inhibitor, ketoconazole on the fecal and urinary disposition of docetaxel in cancer patients. Methods: Fifteen patients were treated with docetaxel (100 mg/m2), followed 3 weeks later by a reduced dose in combination with orally administered ketoconazole, or vice versa. Six patients were also administered [3H]-radiolabeled docetaxel. Fecal and urinary specimens, collected up to 72-h post-infusion, were analyzed for cumulative parent drug and radioactivity excretion. Results: Ketoconazole coadministration increased fecal parent drug excretion twofold from 2.6 ± 2.8 to 5.2 ± 5.4% (mean ± SD, P = 0.03) but did not affect urinary parent drug excretion (P = 0.69). The sum of fecal and urinary parent drug excretion was 5.3 ± 3.0% for docetaxel alone and 7.8 ± 5.6% in the presence of ketoconazole, respectively (P = 0.04). Total recovered radioactivity values were 45.8 ± 19.1 and 32.4 ± 19.7%, respectively (P = 0.23). Conclusion: CYP3A-inhibition by ketoconazole increases fecal parent drug excretion twofold in cancer patients. A more pronounced increase was not achieved, most likely due to concomitant intestinal ABCB1-inhibition.

Cigarette smoking and irinotecan treatment: Pharmacokinetic interaction and effects on neutropenia (Article)

2007-07-01T00:00:00Z

Purpose: Several constituents of cigarette smoke are known to interact with drug metabolizing enzymes and potentially affect treatment outcome with substrate drugs. The purpose of this study was to determine the effects of cigarette smoking on the pharmacokinetics and adverse effects of irinotecan. Patients and Methods: A total of 190 patients (49 smokers, 141 nonsmokers) treated with irinotecan (90-minute intravenous administration on a 3-week schedule) were evaluated for pharmacokinetics. Complete toxicity data were available in a subset of 134 patients receiving 350 mg/m2or 600 mg flat-fixed dose irinotecan. Results: In smokers, the dose-normalized area under the plasma concentration-time curve of irinotecan was significantly lower (median, 28.7 v 33.9 ng·h/mL/mg; P = .001) compared with nonsmokers. In addition, smokers showed an almost 40% lower exposure to SN-38 (median, 0.54 v 0.87 ng·h/mL/mg; P < .001) and a higher relative extent of glucuronidation of SN-38 into SN-38G (median, 6.6 v 4.5; P = .006). Smokers experienced considerably less hematologic toxicity. In particular, the incidence of grade 3 to 4 neutropenia was 6% in smokers versus 38% in nonsmokers (odds ratio [OR], 0.10; 95% CI, 0.02 to 0.43; P < .001). There was no significant difference in incidence of delayed-onset diarrhea (6% v 15%; OR, 0.34; 95% CI, 0.07 to 1.57; P = .149). Conclusion: This study indicates that smoking significantly lowers both the exposure to irinotecan and treatment-induced neutropenia, indicating a potential risk of treatment failure. Although the underlying mechanism is not entirely clear, modulation of CYP3A and uridine diphosphate glucuronosyltransferase isoform 1A1 may be part of the explanation. The data suggest that additional investigation is warranted to determine whether smokers are at increased risk for treatment failure.

Effects of the renin-angiotensin system genes and salt sensitivity genes on blood pressure and atherosclerosis in the total population and patients with type 2 diabetes (Article)

2007-07-01T00:00:00Z

Most studies on the genetic determinants of blood pressure and vascular complications of type 2 diabetes have focused on the effects of single genes. These studies often have yielded conflicting results. Therefore, we examined the combined effects of three renin-angiotensin system (RAS) genes and three salt sensitivity genes in relation to blood pressure and atherosclerosis in the total population and type 2 diabetic patients. The study was a part of the Rotterdam Study, a population-based cohort study. We have genotyped three RAS gene polymorphisms and three salt sensitivity gene polymorphisms. Diabetic patients with three risk genotypes of the RAS genes had a 6.9 mmHg higher systolic blood pressure (P for trend = 0.04) and a 6.0 mmHg higher pulse pressure (P for trend = 0.03) than those who did not carry any risk genotypes. Diabetic patients with three risk genotypes of the salt sensitivity genes had a 9.0 mmHg higher systolic blood pressure (P = 0.19) and a 13.1 mmHg higher pulse pressure (P = 0.02). Diabetic patients who carried three risk genotypes for the RAS genes had a higher mean intima-media thickness than those with two risk genotypes (mean difference 0.04 mm, P = 0.02). We found that among type 2 diabetic patients, mean systolic blood pressure, pulse pressure, and risk of hypertension increased with the number of risk genotypes for the RAS genes and the salt sensitivity genes.

The risk of myocardial infarction in patients with reduced activity of cytochrome P450 2C9 (Article)

2007-07-01T00:00:00Z

OBJECTIVE: The aim of the present follow-up study was to investigate whether the enzyme activity of the human cytochrome P450 (CYP) 2C9 isoenzyme is associated with myocardial infarction. METHODS: We investigated whether the variant alleles CYP2C9*2 and CYP2C9*3 or the use of CYP2C9 substrates or inhibitors was associated with an increased risk of myocardial infarction in 2210 men and 3534 women from the Rotterdam Study, a prospective population-based cohort study of individuals aged 55 years or older. RESULTS: In women, the use of CYP2C9 substrates or inhibitors was significantly associated with incident myocardial infarction with a hazard ratio of 2.48 (95% confidence interval: 1.55-3.96). Within the group of female carriers of a variant allele, the use of CYP2C9 substrates or inhibitors was associated with a fourfold increased risk of myocardial infarction (hazard ratio 3.86, 95% confidence interval: 1.93-7.75), as compared with non-use. Neither the use of CYP2C9 inhibitors or substrates nor the variant CYP2C9 alleles were associated with an increased risk of myocardial infarction in men. CONCLUSIONS: Drugs that are metabolized by CYP2C9 increase the risk of myocardial infarction in women. This risk was even higher in women with allelic variants of CYP2C9 with reduced enzyme activity.

A new CYP3A5 variant, CYP3A5*11, is shown to be defective in nifedipine metabolism in a recombinant cDNA expression system (Article)

2007-01-08T00:00:00Z

A new CYP3A5 variant, CYP3A5*11, was found in a white European subject by DNA sequencing. The CYP3A5*11 allele contains a single nucleotide polymorphism (SNP) (g.3775A>G) in exon 2, which results in a Tyr53Cys substitution, and a g.6986A>G splice change, the latter SNP previously reported in the defective CYP3A5*3 allele. However, the CYP3A5*3 is not a null allele because this variant is associated with leaky splicing, resulting in small amounts of functional protein still being produced. Therefore, we constructed a cDNA coding for the newly identified CYP3A5.11 protein by site-directed mutagenesis, expressed it in Escherichia coli, and partially purified it. Whereas bacteria transformed with wild-type CYP3A5*1 cDNA expressed predominantly cytochrome P450 (P450), those transfected with CYP3A5*11 expressed a significant amount of denatured cytochrome P420 in addition to P450, suggesting the protein to be unstable. CYP3A5.11 exhibited a 38% decrease in the Vmaxfor nifedipine metabolism, a 2.7-fold increase in the Km, and a 4.4-fold decrease in the CLintof nifedipine compared with CYP3A5.1. A polymerase chain reaction-restriction fragment length polymorphism genotyping procedure was developed and used to genotype DNA of 500 white individuals for CYP3A5*11. No additional examples of this allele were identified. In summary, individuals carrying the rare CYP3A5*11 allele are predicted to have lower metabolism of CYP3A5 substrates than individuals expressing CYP3A5*3.

Prophylaxis of irinotecan-induced diarrhea with neomycin and potential role for UGT1A1*28 genotype screening: a double-blind, randomized, placebo-controlled study. (Article)

2006-09-18T00:00:00Z

OBJECTIVE: Delayed-type diarrhea is a common side effect of irinotecan and is associated with a bacterial-mediated formation of the active irinotecan metabolite SN-38 from its glucuronide conjugate in the intestine. Based on a pilot study, we hypothesized that concomitant administration of the antibiotic neomycin would diminish exposure of the gut to SN-38 and ameliorate the incidence and severity of diarrhea. PATIENTS AND METHODS: Patients were treated with irinotecan in a multicenter, double-blind, randomized, placebo-controlled trial. Eligible patients received irinotecan (350 mg/m(2) once every 3 weeks) combined with neomycin (660 mg three times daily for three consecutive days, starting 2 days before chemotherapy) or combined with placebo. Blood samples were obtained for additional pharmacokinetic and pharmacogenetic analyses. RESULTS: Sixty-two patients were evaluable for the toxicity analysis. Baseline patient characteristics, systemic SN-38 exposure, and UGT1A1*28 genotype status (i.e., an additional TA repeat in the promoter region of uridine diphosphate-glucuronosyltransferase isoform 1A1) were similar in both arms. Although distribution, severity, and duration of delayed-type diarrhea did not differ significantly between arms, grade 3 diarrhea tended to be less frequent in the neomycin arm. The presence of at least one UGT1A1*28 allele was strongly related to the incidence of grade 2-3 diarrhea. In the neomycin arm, grade 2 nausea was significantly more common. CONCLUSION: Our results do not suggest a major role for neomycin as prophylaxis for irinotecan-induced delayed-type diarrhea. It is suggested that the UGT1A1*28 genotype status could be used as a screening tool for a priori prevention of irinotecan-induced delayed-type diarrhea.

Acute dystonic reaction to metoclopramide in patients carrying homozygous cytochrome P450 2D6 genetic polymorphisms (Article)

2006-01-01T00:00:00Z

BACKGROUND: Extrapyramidal syndromes (EPS) are clinically relevant side effects of metoclopramide which are often not anticipated. PATIENTS AND METHODS: Two patients who received metoclopramide developed an acute dystonic reaction. Symptoms disappeared after biperiden or trihexyphenidyl were given. Molecular analysis of the CYP2D6 gene was performed using a PCR-based method. RESULTS: Both patients were homozygous for inactive CYP2D6 alleles (CYP2D6*4/*4 and CYP2D6*4/*5), which are associated with slow drug metabolism. CONCLUSION: Metoclopramide-induced acute dystonic reactions may occur in patients carrying a CYP2D6 genetic polymorphism.

A common polymorphism in the CYP3A7 gene is associated with a nearly 50% reduction in serum dehydroepiandrosterone sulfate levels. (Article)

2005-09-01T00:00:00Z

CONTEXT: CYP3A7, expressed in the human fetal liver and normally silenced after birth, plays a major role in the 16alpha-hydroxylation of dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), and estrone. Due to a replacement of part of the CYP3A7 promoter with a sequence identical with the same region in the CYP3A4 promoter (referred to as CYP3A7*1C), some individuals still express a variant of the CYP3A7 gene later in life. OBJECTIVE: The objective of this study was to examine the effect of the CYP3A7*1C polymorphism on serum steroid hormone levels. DESIGN, SETTING, PARTICIPANTS: Two population-based cohort studies were performed. Study group 1 consisted of 208 subjects randomly selected from the Rotterdam Study, and study group 2 consisted of 345 elderly independently living men. MAIN OUTCOME MEASURES: Serum DHEA(S), androstenedione, estradiol, estrone, and testosterone levels were the main outcome measures. RESULTS: In study groups 1 and 2, heterozygous CYP3A7*1C carriers had almost 50% lower DHEAS levels compared with homozygous carriers of the reference allele [study group 1, 1.74 +/- 0.25 vs. 3.33 +/- 0.15 micromol/liter (P = 0.02); study group 2, 2.09 +/- 0.08 vs. 1.08 +/- 0.12 micromol/liter (P < 0.001)]. No differences in circulating DHEA, androstenedione, estradiol, or testosterone levels were found. However, in study group 2, serum estrone levels were lower in heterozygous CYP3A7*1C carriers compared with homozygous carriers of the reference allele (0.11 +/- 0.002 vs. 0.08 +/- 0.006 nmol/liter; P < 0.001). CONCLUSION: The CYP3A7*1C polymorphism causes the persistence of enzymatic activity of CYP3A7 during adult life, resulting in lower circulating DHEAS and estrone levels.

Phase I pharmacokinetic, food effect, and pharmacogenetic study of oral irinotecan given as semisolid matrix capsules in patients with solid tumors. (Article)

2005-02-15T00:00:00Z

PURPOSE: To characterize the maximum-tolerated dose, recommended dose, dose-limiting toxicities (DLT), pharmacokinetic profile, and food effect of orally administered irinotecan formulated as new semisolid matrix capsules. EXPERIMENTAL DESIGN: Irinotecan was given orally in fasted patients once daily for 5 consecutive days and repeated every 3 weeks. Patients were randomly assigned to take the drug along with a high-fat, high-calorie breakfast for the administration at day 1 of the first or second cycle. Dosages tested were 70 and 80 mg/m(2)/day. RESULTS: Twenty-five patients received 101 cycles of therapy (median two cycles, range 1-15). During the first cycle, grade 3 delayed diarrhea and grade 3 fever were the DLTs at the dosage of 80 mg/m(2)/day in three out of five patients. Hematologic and nonhematologic toxicities were mild to moderate. Exposure to the active metabolite SN-38 was relatively high compared with i.v. infusion, but no relevant accumulation was observed. Food had no significant effect on irinotecan pharmacokinetics. One confirmed partial remission and 10 disease stabilizations were observed in previously treated patients. No association was found between the UGT1A1*28 genotype and the risk of severe irinotecan-induced toxicity. CONCLUSIONS: For oral irinotecan, a dose of 70 mg/m(2)/day for 5 consecutive days every 3 weeks is recommended for further studies. Delayed diarrhea was the main DLT, similar to that observed with intravenously administered irinotecan. This study confirms that oral administration of irinotecan is feasible and may have favorable pharmacokinetic characteristics.

Prediction of irinotecan pharmacokinetics by use of cytochrome P450 3A4 phenotyping probes. (Article)

2004-11-03T00:00:00Z

BACKGROUND: Irinotecan is a topoisomerase I inhibitor that has been approved for use as a first- and second-line treatment for colorectal cancer. The response to irinotecan is variable, possibly because of interindividual variation in the expression of the enzymes that metabolize irinotecan, including cytochrome P450 3A4 (CYP3A4) and uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1). We prospectively explored the relationships between CYP3A phenotype, as assessed by erythromycin metabolism and midazolam clearance, and the metabolism of irinotecan and its active metabolite SN-38. METHODS: Of the 30 white cancer patients, 27 received at least two treatments with irinotecan administered as one 90-minute infusion (dose, 600 mg) with 3 weeks between treatments, and three received only one treatment. Before the first and second treatments, patients underwent an erythromycin breath test and a midazolam clearance test as phenotyping probes for CYP3A4. Erythromycin metabolism was assessed as the area under the curve for the flux of radioactivity in exhaled CO2 within 40 minutes after administration of [N-methyl-14C]erythromycin. Midazolam and irinotecan were measured by high-performance liquid chromatography. Genomic DNA was isolated from blood and screened for genetic variants in CYP3A4 and UGT1A1. All statistical tests were two-sided. RESULTS: CYP3A4 activity varied sevenfold (range = 0.223%-1.53% of dose) among patients, whereas midazolam clearance varied fourfold (range = 262-1012 mL/min), although intraindividual variation was small. Erythromycin metabolism was not statistically significantly associated with irinotecan clearance (P = .090), whereas midazolam clearance was highly correlated with irinotecan clearance (r = .745, P<.001). In addition, the presence of a UGT1A1 variant with a (TA)7 repeat in the promoter (UGT1A1*28) was associated with increased exposure to SN-38 (435 ng x h/mL, 95% confidence interval [CI] = 339 to 531 ng x h/mL in patients who are homozygous for wild-type UGT1A1; 631 ng x h/mL, 95% CI = 499 to 762 ng . h/mL in heterozygous patients; and 1343 ng x h/mL, 95% CI = 0 to 4181 ng x h/mL in patients who are homozygous for UGT1A1*28) (P = .006). CONCLUSION: CYP3A4 phenotype, as assessed by midazolam clearance, is statistically significantly associated with irinotecan pharmacokinetics. Evaluation of midazolam clearance combined with UGT1A1*28 genotyping may assist with optimization of irinotecan chemotherapy.

Circulating free insulin-like growth factor (IGF)-I, total IGF-I, and IGF binding protein-3 levels do not predict the future risk to develop prostate cancer: results of a case-control study involving 201 patients within a population-based screening with a 4-year interval. (Article)

2004-09-01T00:00:00Z

Recent studies have reported that serum IGF-I levels in the highest quartile of the normal range and IGF binding protein-3 (IGFBP-3) in the lowest quartile of the normal range are associated with an increased risk of future prostate cancer and/or presence of prostate cancer. It has also been suggested that the measurement of circulating total IGF-I concentrations might be a useful tool for the early detection of prostate cancer in men with moderately increased prostate-specific antigen (PSA) levels.To determine whether circulating free IGF-I, total IGF-I, and IGFBP-3 levels can predict future prostate cancer risk, we prospectively studied prostate cancer characteristics in a cohort of men during two rounds (mean interval, 4 yr) of a population-based screening study for prostate cancer. Two hundred one prostate cancer cases were detected at the second-round screening (aged 55-70 yr), and all these subjects were enrolled in the case group for the present study. Prostate cancer had been confirmed by biopsy in all cases. These 201 subjects were matched with the 201 nonprostate cancer cases by age, serum PSA range at the first-round screening (PSA < 2 ng/ml, n = 67; PSA = 2-3 ng/ml, n = 67; and PSA = 3-4 ng/ml, n = 67), and residence area.At baseline, total IGF-I, free IGF-I, and IGFBP-3 levels and prostate volume of cases with prostate cancer were not different from those of healthy controls. PSA velocity was significantly different between cases and controls (P < 0.001).Stepwise forward logistic regression analysis showed that only PSA levels at baseline and PSA at round 2 after 4 yr are good predictors of prostate cancer, whereas total IGF-I, free IGF-I, and IGFBP-3 did not predict the development of prostate cancer.Only one of the 201 subjects with prostate cancer had metastases. Within the subjects with prostate cancer, there were no differences of IGF-I parameters with different tumor node metastasis categories and/or Gleason scores.Our study suggests that the measurement of serum IGF-I and/or IGFBP-3 concentrations in addition to PSA does not improve the identification of men at high risk to develop early stages of prostate cancer. In addition, our results indicate that the endocrine IGF-I system is not directly involved in the growth of the early stages of prostate cancer.

Sequencing: not always the "gold standard". (Article)

2004-01-01T00:00:00Z

The risk of bleeding complications in patients with cytochrome P450 CYP2C92 or CYP2C93 alleles on acenocoumarol of phenprocoumon (Article)

2004-01-01T00:00:00Z

The principal enzyme involved in coumarin metabolism is CYP2C9. Allelic variants of CYP2C9, CYP2C9*2 and CYP2C9*3, code for enzymes with reduced activity. Despite increasing evidence that patients with these genetic variants require lower maintenance doses of anticoagulant therapy, there is lack of agreement among studies on the risk of bleeding and CYP2C9 polymorphisms. It was, therefore, our objective to study the effect of the CYP2C9 polymorphisms on bleeding complications during initiation and maintenance phases of coumarin anticoagulant therapy. The design of the study was a population-based cohort in a sample of the Rotterdam Study, a study in 7,983 subjects. All patients who started treatment with acenocoumarol or phenprocoumon in the study period from January 1, 1991 through December 31, 1998 and for whom INR data were available were included. Patients were followed until a bleeding complication, the end of their treatment, death or end of the study period. Proportional hazards regression analysis was used to estimate the risk of a bleeding complication in relation to CYP2C9 genotype after adjustment for several potentially confounding factors such as age, gender, target INR level, INR, time between INR measurements, and aspirin use. The effect of variant genotype on bleeding risk was separately examined during the initiation phase of 90 days after starting therapy with coumarins. The 996 patients with analysable data had a mean follow-up time of 481 days (1.3 years); 311 (31.2%) had at least 1 variant CYP2C9 allele and 685 (68.8%) had the wild type genotype. For patients with the wild type genotype, the rate of minor bleeding, major bleeding and fatal bleeding was 15.9, 3.4 and 0.2 per 100 treatment-years, respectively. For patients with a variant genotype, the rate of minor, major and fatal bleeding was 14.6, 5.4 and 0.5 per 100 treatment-years. Patients with a variant genotype on acenocoumarol had a significantly increased risk for a major bleeding event (HR 1.83, 95% CI: 1.01-3.32). During the initiation phase of therapy we found no effect of variant genotype on bleeding risk. In this study among outpatients of an anticoagulation clinic using acenocoumarol or phenprocoumon, having a variant allele of CYP2C9 was associated with an increased risk of major bleeding events in patients on acenocoumarol, but not in patients on phenprocoumon. Although one might consider the assessment of the CYP2C9 genotype of a patient for dose adjustment before starting treatment with acenocoumarol, a prospective randomised trial should demonstrate whether this reduces the increased risk of major bleeding events.

CYP3A5 variant allele frequencies in Dutch Caucasians (Article)

2002-01-01T00:00:00Z

BACKGROUND: Enzymes of the cytochrome P450 3A (CYP3A) family are responsible for the metabolism of >50% of currently prescribed drugs. CYP3A5 is expressed in a limited number of individuals. The absence of CYP3A5 expression in approximately 70% of Caucasians was recently correlated to a genetic polymorphism (CYP3A5*3). Because CYP3A5 may represent up to 50% of total CYP3A protein in individuals polymorphically expressing CYP3A5, it may have a major role in variation of CYP3A-mediated drug metabolism. Using sequencing, have been identified (Hustert et al. Pharmacogenetics 2001;11:773-9; Kuehl et al. Nat Genet 2001;27:383-91) variant alleles *2 through *7 for CYP3A5. Detection of CYP3A5 variant alleles, and knowledge about their allelic frequency in specific ethnic groups, is important to establish the clinical relevance of screening for these polymorphisms to optimize pharmacotherapy. METHODS: In a group of 500 healthy Dutch Caucasian blood donors, we determined the allelic frequency of the CYP3A5*2, *3, *4, *5, *6, and *7 alleles by use of newly developed PCR-restriction fragment length polymorphism assays. RESULTS: The frequency of the defective CYP3A5*3 allele in the Dutch Caucasian population was 91%, followed by the CYP3A5*2 (1%) and CYP3A5*6 (0.1%) alleles. The CYP3A5*4, *5, and *7 alleles were not detected. CONCLUSIONS: On the basis of its allelic frequency, screening for the CYP3A5*3 allele in the Caucasian population is extremely relevant. In addition, screening for the CYP3A5*2 allele may be taken into consideration in individuals heterozygous for the CYP3A5*3 allele. The CYP3A5*4, *5, *6, and *7 alleles have low allelic frequencies that do not support initial screening.

The CYP3A4*3 allele: is it really rare? (Article)

2001-01-01T00:00:00Z

CYP3A4-V polymorphism detection by PCR-restriction fragment length polymorphism analysis and its allelic frequency among 199 Dutch Caucasians (Article)

2000-01-01T00:00:00Z

Optimization of apolipoprotein(a) genotyping with pulsed field gel electrophoresis (Article)

1999-01-01T00:00:00Z

BACKGROUND: Increased lipoprotein(a) is a risk factor for atherosclerosis, and its concentration in serum is inversely correlated with the size of the apoliprotein(a) [apo(a)] component. The size of the apo(a) gene is determined mainly by the Kringle IV size polymorphism. We have optimized and characterized pulsed field gel electrophoresis (PFGE) for apo(a) genotyping. METHODS: Established PFGE protocols were adjusted. The changes included the following: (a) increased DNA yields by the use of all leukocytes for isolation from either 3 mL of fresh EDTA whole blood or 250 microL of frozen buffy coats; (b) increased efficiency of Kpn1 digestion by the inclusion of a digestion buffer wash; (c) reduction of assay time by the use of capillary blotting; (d) increased sensitivity by the use of four digoxigenin-labeled apo(a) probes; and (e) identification using a single film by the inclusion of a digoxigenin-labeled lambda marker probe in addition to apo(a) probes in the hybridization mix. RESULTS: In older Caucasians, 93% (buffy coats, n=468) were heterozygous for apo(a) gene size. An inverse correlation between serum lipoprotein(a) and the sum of Kringle IV alleles was found (y = -23x + 1553; r = -0.442; n = 468). Gel-to-gel variation was minimal (3%). Imprecision (SD) was one Kringle IV repeat (control sample containing eight fragments of 72-233 kb; n=34 electrophoretic runs). CONCLUSIONS: The practicality and sensitivity of the apo(a) genotyping technique by PFGE were improved, and accuracy and reproducibility were preserved. The optimized procedure is promising for apo(a) genotyping on frozen buffy coats from large epidemiological studies.

Human activin-A is expressed in the atherosclerotic lesion and promotes the contractile phenotype of smooth muscle cells (Article)

1999-01-01T00:00:00Z

Activin is a member of the transforming growth factor-beta superfamily, and it modulates the proliferation and differentiation of various target cells. In this study, we investigated the role of activin in the initiation and progression of human atherosclerosis. The expression of activin, its physiological inhibitor follistatin, and activin receptors were assayed in human vascular tissue specimens that represented various stages of atherogenesis. In situ hybridization experiments revealed activin mRNA in endothelial cells and macrophages and a strong induction of activin expression in neointimal smooth muscle cells from the early onset of atherogenesis. We developed an "in situ free-activin binding assay" by using biotinylated follistatin, which allowed us to detect bioactive activin at specific sites in atherosclerotic lesions. The mRNAs encoding the activin receptors are expressed similarly in normal and atherosclerotic tissue, which indicates that activin-A signaling in atherogenesis is most likely dependent on changes in growth factor concentrations rather than on receptor levels. In vitro, activin induces the contractile, nonproliferative phenotype in cultured smooth muscle cells, as is reflected by increased expression of smooth muscle-specific markers (SMalpha-actin and SM22alpha). Our data provide evidence that activin induces redifferentiation of neointimal smooth muscle cells, and we hypothesize that activin is involved in plaque stabilization.

Temporal changes in inhibin subunit mRNAs during atresia of preovulatory follicles in the rat (Article)

1998-01-01T00:00:00Z

This study aimed to investigate the time course of disappearance of the mRNAs of the various subunits of inhibin in follicles which become atretic. An animal model was used in which atresia of preovulatory follicles could be studied in a chronological order. Injection of gonadotrophin-releasing hormone (GnRH) antagonist (20 microg) at the morning of pro-oestrus (P) blocked ovulation and the 10-12 preovulatory follicles became gradually atretic. A second injection was given the next day to prevent delayed ovulation. The rate of atresia could be delayed by simultaneous administration of a subovulatory dose of human chorionic gonadotrophin (hCG) (0.5 IU) and could be advanced by administration of a fivefold larger amount of GnRH antagonist. Functional activity of follicles becoming atretic was studied by measuring oestradiol production after incubation of individual follicles for 4 h. Follicles isolated 24 h after the first injection of GnRH antagonist (P+24) already secreted significantly less oestradiol in vitro than follicles isolated at pro-oestrus, although they were morphologically not different from pro-oestrous follicles. Follicles isolated at P+24 from hCG-treated rats secreted more oestradiol compared with follicles from rats not treated with hCG. In contrast, follicles isolated at P+24 from rats that were given a fivefold larger amount of GnRH antagonist secreted less oestradiol. Once this model was validated, temporal changes in inhibin subunit mRNAs in follicles undergoing atresia were measured by in situ hybridization and RNase protection assay. In situ hybridization showed abundant alpha- and betaA-subunit mRNA in the whole granulosa layer of preovulatory follicles at P and P+24, while betaB-subunit mRNA was restricted to the antral layer and cumulus. At P+48 the amount of alpha- and betaA-subunit mRNA had declined and was restricted to the cumulus, whereas betaB-subunit mRNA was absent. In the atretic follicles present at P+72 and P+96, mRNAs of all three inhibin subunits were absent. Administration of 0.5 IU hCG delayed the decline in the amount of alpha, betaA and betaB mRNA in preovulatory follicles at P+48. RNase protection assay of inhibin subunits in isolated follicles revealed no changes between P and P+24. However, at P+48, the mRNAs of alpha- and betaA-subunits were decreased. Expression of the mRNA of betaB-subunit declined gradually from P to P+48. The present study demonstrates that in follicles which are becoming atretic, mRNAs of alpha- and betaA-subunits decline simultaneously with the appearance of pycnotic cells in the granulosa layer, while betaB-subunit mRNA declines earlier, simultaneously with the decrease in the ability to secrete oestradiol in vitro.

Inhibin interferes with activin signaling at the level of the activin receptor complex in Chinese hamster ovary cells (Article)

1997-01-01T00:00:00Z

To gain more insight in the mechanism of action of inhibin, we studied the effect of inhibin on activin signaling in Chinese hamster ovary cells. Inhibin specifically counteracted activin-induced expression of a plasminogen activator inhibitor 1 promoter element (3TP) and of the junB gene, but was ineffective when the responses were induced by transforming growth factor-beta. This indicates that inhibin acts only on the activin-specific part of these signaling cascades. Using a constitutively active activin type IB receptor we determined whether inhibin acted at the level of the activin-receptor complex or downstream of it. The mutant activin receptor stimulated the expression of the 3TP promoter in the absence of activin. This stimulation was insensitive to inhibin, indicating that inhibin acts exclusively at or upstream of this activin type I receptor. In addition, competition studies using labeled activin showed that inhibin displaced activin from the activin type II receptors, especially from the activin type IIB receptor, but not from the type I receptors. In conclusion, these data show that in Chinese hamster ovary cells inhibin acts directly at the activin receptor complex, most likely through displacement of activin from the activin type II receptor.

Schaik, R.H.N. van

Prospective Multicenter Evaluation of the Beckman Coulter Prostate Health Index Using WHO Calibration (Article)

Doubt about the feasibility of preemptive genotyping (Article)

CYP3A4 intron 6 C>T SNP (CYP3A4*22) encodes lower CYP3A4 activity in cancer patients, as measured with probes midazolam and erythromycin (Article)

Reply to F.L. Opdam et al (Article)

The interactions of age, genetics, and disease severity on tacrolimus dosing requirements after pediatric kidney and liver transplantation (Article)

Age and CYP3A5 genotype affect tacrolimus dosing requirements after transplant in pediatric heart recipients (Article)

Novel CYP3A4 intron 6 single nucleotide polymorphism is associated with simvastatin-mediated cholesterol reduction in the Rotterdam Study (Article)

ATP-binding cassette transporters as pharmacogenetic biomarkers for kidney transplantation (Article)

Dextromethorphan as a phenotyping test to predict endoxifen exposure in patients on tamoxifen treatment (Article)

CYP3A5, ABCB1, and SLCO1B1 polymorphisms and pharmacokinetics and virologic outcome of lopinavir/ritonavir in HIV-infected children (Article)

The CYP2C19*2 genotype predicts tamoxifen treatment outcome in advanced breast cancer patients (Article)

CYP3A5 genotype is not related to the intrapatient variability of tacrolimus clearance (Article)

Pharmacogenetics: From bench to byte an update of guidelines (Article)

A multicenter study of [-2]pro-prostate specific antigen combined with prostate specific antigen and free prostate specific antigen for prostate cancer detection in the 2.0 to 10.0 ng/ml prostate specific antigen range (Article)

Pharmacogenomics and personalized medicine in clinical practice (Article)

General maternal medication use, folic acid, the MDR1 C3435T polymorphism, and the risk of a child with a congenital heart defect (Article)

OCT1 polymorphism is associated with response and survival time in anti-Parkinsonian drug users (Article)

Simultaneous quantification of dextromethorphan and its metabolites dextrorphan, 3-methoxymorphinan and 3-hydroxymorphinan in human plasma by ultra performance liquid chromatography/tandem triple-quadrupole mass spectrometry (Article)

Practical recommendations for pharmacogenomics-based prescription: 2010 ESF-UB Conference on Pharmacogenetics and Pharmacogenomics (Article)

Polymorphisms in the multidrug resistance gene MDR1 (ABCB1) predict for molecular resistance in patients with newly diagnosed chronic myeloid leukemia receiving high-dose imatinib (Article)

Cytochrome P450 3A gene variation, steroid hormone serum levels and prostate cancer - The Rotterdam Study (Article)

On the use of prostate-specific antigen for screening of prostate cancer in European Randomised Study for Screening of Prostate Cancer (Article)

Nucleic acid reference materials (NARMs): Definitions and issues (Article)

CYP2C19*2 polymorphism is associated with increased survival in breast cancer patients using tamoxifen (Article)

Effects of mannose-binding lectin polymorphisms on irinotecan-induced febrile neutropenia (Article)

The impact of CYP2D6-predicted phenotype on tamoxifen treatment outcome in patients with metastatic breast cancer (Article)

Dihydropyrimidine dehydrogenase polymorphisms and fluoropyrimidine toxicity: ready for routine clinical application within personalized medicine? (Article)

Polymorphisms in type i and II inosine monophosphate dehydrogenase genes and association with clinical outcome in patients on mycophenolate mofetil (Article)

Prostate-Specific Antigen (PSA) Isoform p2PSA in Combination with Total PSA and Free PSA Improves Diagnostic Accuracy in Prostate Cancer Detection (Article)

Lower atovaquone/proguanil concentrations in patients taking efavirenz, lopinavir/ritonavir or atazanavir/ritonavir (Article)

Polymorphisms in genes involved in vincristine pharmacokinetics or pharmacodynamics are not related to impaired motor performance in children with leukemia (Article)

CYP2D6 4, CYP3A5 3 and ABCB1 3435T polymorphisms and drug-related falls in elderly people (Article)

A comparison of the acid-inhibitory effects of esomeprazole and pantoprazole in relation to pharmacokinetics and CYP2C19 polymorphism (Article)

Influence of genetic variation in CYP3A4 and ABCB1 on dose decrease or switching during simvastatin and atorvastatin therapy (Article)

Interaction between polymorphisms in the OCT1 and MATE1 transporter and metformin response (Article)

Common genetic variation in the ABCB1 gene is associated with the cholesterol-lowering effect of simvastatin in males (Article)

Considerations for the development of a reference method for sequencing of haploid DNA -an opinion paper on behalf of the IFCC committee on molecular diagnostics (Article)

The CYP2D6 4 polymorphism affects breast cancer survival in tamoxifen users (Article)

Maternal medication use, carriership of the ABCB1 3435C > T polymorphism and the risk of a child with cleft lip with or without cleft palate (Article)

A genome-wide association study of acenocoumarol maintenance dosage. (Article)

UGT1A9 -275T>A/-2152C>T Polymorphisms Correlate With Low MPA Exposure and Acute Rejection in MMF/Tacrolimus-Treated Kidney Transplant Patients (Article)

Interpatient variability in IMPDH activity in MMF-treated renal transplant patients is correlated with IMPDH type II 3757T>C polymorphism (Article)

Variation in the CYP2D6 gene is associated with a lower serum sodium concentration in patients on antidepressants (Article)

Association between the CYP2D6*4 polymorphism and depression or anxiety in the elderly (Article)

Genotypes associated with reduced activity of VKORC1 and CYP2C9 and their modification of acenocoumarol anticoagulation during the initial treatment period (Article)

Efavirenz dose reduction to 200 mg once daily in a patient treated with rifampicin (Article)

Genetic variation in the multidrug and toxin extrusion 1 transporter protein influences the glucose-lowering effect of metformin in patients with diabetes: A preliminary study (Article)

Pharmacogenetic pathway analysis of docetaxel elimination (Article)

No modification of the beneficial effect of NSAIDs on colorectal cancer by CYP2C9 genotype (Article)

Genetic variation in the CYP2D6 gene is associated with a lower heart rate and blood pressure in β-blocker users (Article)

Clinical impact of new prostate-specific antigen WHO standardization on biopsy rates and cancer detection (Article)

A drug transporter for all ages? ABCB1 and the developmental pharmacogenetics of cyclosporine (Article)

Postmenstrual age and CYP2D6 polymorphisms determine tramadol O-demethylation in critically ill neonates and infants (Article)

Association of graded allele-specific changes in CYP2D6 function with imipramine dose requirement in a large group of depressed patients (Article)

CYP450 pharmacogenetics for personalizing cancer therapy (Article)

Effect of CYP2C19*2 and *17 mutations on pharmacodynamics and kinetics of proton pump inhibitors in Caucasians (Article)

Covariates of tramadol disposition in the first months of life (Article)

Influence of the CYP2D6*4 polymorphism on dose, switching and discontinuation of antidepressants (Article)

Vitamin K epoxide reductase complex subunit 1 (VKORC1) polymorphism and aortic calcification: The Rotterdam study (Article)

CYP3A5 genotype is not associated with a higher risk of acute rejection in tacrolimus-treated renal transplant recipients (Article)

Common ATP-binding cassette B1 variants are associated with increased digoxin serum concentration (Article)

UGT2B7 promoter variant -840G>A contributes to the variability in hepatic clearance of morphine in patients with sickle cell disease (Article)

Cytochrome P450 2C9 *2 and *3 polymorphisms and the dose and effect of sulfonylurea in type II diabetes mellitus (Article)

MUC1 568 A/G genotype-dependent Cancer Antigen 15-3 levels in breast cancer patients (Article)

Hepatotoxicity of oral and intravenous voriconazole in relation to cytochrome P450 polymorphisms (Article)

Tubular and Interstitial Nephrocalcinosis (Article)

Influence of ketoconazole on the fecal and urinary disposition of docetaxel (Article)

Cigarette smoking and irinotecan treatment: Pharmacokinetic interaction and effects on neutropenia (Article)

Effects of the renin-angiotensin system genes and salt sensitivity genes on blood pressure and atherosclerosis in the total population and patients with type 2 diabetes (Article)

The risk of myocardial infarction in patients with reduced activity of cytochrome P450 2C9 (Article)

A new CYP3A5 variant, CYP3A5*11, is shown to be defective in nifedipine metabolism in a recombinant cDNA expression system (Article)

Prophylaxis of irinotecan-induced diarrhea with neomycin and potential role for UGT1A1*28 genotype screening: a double-blind, randomized, placebo-controlled study. (Article)

Acute dystonic reaction to metoclopramide in patients carrying homozygous cytochrome P450 2D6 genetic polymorphisms (Article)

A common polymorphism in the CYP3A7 gene is associated with a nearly 50% reduction in serum dehydroepiandrosterone sulfate levels. (Article)

Phase I pharmacokinetic, food effect, and pharmacogenetic study of oral irinotecan given as semisolid matrix capsules in patients with solid tumors. (Article)

Prediction of irinotecan pharmacokinetics by use of cytochrome P450 3A4 phenotyping probes. (Article)

Circulating free insulin-like growth factor (IGF)-I, total IGF-I, and IGF binding protein-3 levels do not predict the future risk to develop prostate cancer: results of a case-control study involving 201 patients within a population-based screening with a 4-year interval. (Article)

Sequencing: not always the "gold standard". (Article)

The risk of bleeding complications in patients with cytochrome P450 CYP2C9*2 or CYP2C9*3 alleles on acenocoumarol of phenprocoumon (Article)

Effect of CYP2C192 and 17 mutations on pharmacodynamics and kinetics of proton pump inhibitors in Caucasians (Article)

Cytochrome P450 2C9 2 and 3 polymorphisms and the dose and effect of sulfonylurea in type II diabetes mellitus (Article)

The risk of bleeding complications in patients with cytochrome P450 CYP2C92 or CYP2C93 alleles on acenocoumarol of phenprocoumon (Article)