Irinotecan pathway genotype analysis to predict pharmacokinetics
PURPOSE: The purpose was to explore the relationships between irinotecan disposition and allelic variants of genes coding for adenosine triphosphate binding cassette transporters and enzymes of putative relevance for irinotecan. EXPERIMENTAL DESIGN: Irinotecan was administered to 65 cancer patients as a 90-min infusion (dose, 200-350 mg/m(2)), and pharmacokinetic data were obtained during the first cycle. All patients were genotyped for variants in genes encoding MDR1 P-glycoprotein (ABCB1), multidrug resistance-associated proteins MRP-1 (ABCC1) and MRP-2 (canalicular multispecific organic anion transporter; ABCC2), breast cancer resistance protein (ABCG2), carboxylesterases (CES1, CES2), cytochrome p450 isozymes (CYP3A4, CYP3A5), UDP glucuronosyltransferase (UGT1A1), and a DNA-repair enzyme (XRCC1), which was included as a nonmechanistic control. RESULTS: Eighteen genetic variants were found in nine genes of putative importance for irinotecan disposition. The homozygous T allele of the ABCB1 1236C>T polymorphism was associated with significantly increased exposure to irinotecan (P = 0.038) and its active metabolite SN-38 (P = 0.031). Pharmacokinetic parameters were not related to any of the other multiple variant genotypes, possibly because of the low allele frequency. The extent of SN-38 glucuronidation was slightly impaired in homozygous variants of UGT1A1*28, although differences were not statistically significant (P = 0.22). CONCLUSIONS: It is concluded that genotyping for ABCB1 1236C>T may be one of the factors assisting with dose optimization of irinotecan chemotherapy in cancer patients. Additional investigation is required to confirm these findings in a larger population and to assess relationships between irinotecan disposition and the rare variant genotypes, especially in other ethnic groups.
|Keywords||*Genotype, ATP-Binding Cassette Transporters/genetics, Adenosine Triphosphate/genetics, Adult, Aged, Alleles, Camptothecin/*analogs & derivatives/*pharmacokinetics/pharmacology, Carboxylesterase/genetics, Cell Line, Tumor, Cytochrome P-450 Enzyme System/genetics, DNA-Binding Proteins/genetics, Female, Gene Frequency, Glucuronic Acids/chemistry, Glucuronosyltransferase/genetics, Homozygote, Humans, Male, Membrane Transport Proteins/genetics, Middle aged, Models, Biological, Multidrug Resistance-Associated Proteins/genetics, Neoplasm Proteins/genetics, P-Glycoprotein/genetics, Phenotype, Polymorphism, Genetic, Protein Binding, Research Support, U.S. Gov't, P.H.S.|
Mathijssen, A.H.J., Marsh, S., Karlsson, M.O., Xie, R., Baker, S.D., Verweij, J., … McLeod, H.L.. (2003). Irinotecan pathway genotype analysis to predict pharmacokinetics. Clinical Cancer Research. Retrieved from http://hdl.handle.net/1765/10220