ABCG2 pharmacogenetics: ethnic differences in allele frequency and assessment of influence on irinotecan disposition.
PURPOSE: The ATP-binding cassette transporter ABCG2 (breast cancer resistance protein) is an efflux protein that plays a role in host detoxification of various xenobiotic substrates, including the irinotecan metabolite 7- ethyl-10-hydroxycamptothecin (SN-38). The ABCG2 421C>A polymorphism has been associated with reduced protein expression and altered function in vitro. The aim of this study was to evaluate the ethnic distribution and potential functional consequence of the ABCG2 421C>A genotype in cancer patients treated with irinotecan. EXPERIMENTAL DESIGN: ABCG2 genotyping was performed using Pyrosequencing on DNA from 88 American Caucasians, 94 African Americans, 938 Africans, and 95 Han Chinese, as well as in 84 European Caucasian patients treated with irinotecan undergoing additional blood sampling for pharmacokinetic studies. RESULTS: Significant differences in allele frequencies were observed between the given world populations (P < 0.001), the variant allele being most common in the Han Chinese population with a frequency as high as 34%. The mean area under the curve of irinotecan and SN-38 were 19,851 and 639 ng x hour/mL, respectively. The frequency of the variant allele (10.7%) was in line with results in American Caucasians. No significant changes in irinotecan pharmacokinetics were observed in relation to the ABCG2 421C>A genotype, although one of two homozygous variant allele carriers showed extensive accumulation of SN-38 and SN-38 glucuronide. CONCLUSIONS: The ABCG2 421C>A polymorphism appears to play a limited role in the disposition of irinotecan in European Caucasians. It is likely that the contribution of this genetic variant is obscured by a functional role of other polymorphic proteins.
|Keywords||*Pharmacogenetics, *Polymorphism, Genetic, ATP-Binding Cassette Transporters/*genetics, Adult, African Continental Ancestry Group, Aged, Antineoplastic Agents, Phytogenic/*pharmacokinetics/pharmacology, Camptothecin/*analogs & derivatives/*pharmacokinetics/pharmacology, Comparative Study, Drug Resistance, Multiple, European Continental Ancestry Group, Female, Gene Frequency, Genotype, Humans, Male, Middle aged, Neoplasm Proteins/*genetics, Neoplasms/*ethnology/*genetics, Research Support, U.S. Gov't, P.H.S.|
|Persistent URL||dx.doi.org/10.1158/1078-0432.CCR-04-0144, hdl.handle.net/1765/13493|
de Jong, F.A., Marsh, S., Mathijssen, A.H.J., King, C-C., Verweij, J., Sparreboom, A., & McLeod, H.L.. (2004). ABCG2 pharmacogenetics: ethnic differences in allele frequency and assessment of influence on irinotecan disposition.. Clinical Cancer Research, 10(17), 5889–5894. doi:10.1158/1078-0432.CCR-04-0144