Genetic Polymorphisms of Metabolic Enzymes and the Pharmacokinetics of Indapamide in Taiwanese Subjects
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To understand the genetic makeup and impact on pharmacokinetics (PK) in the Taiwanese population, we analyzed the pharmacogenetic (PG) profile and demonstrated its effects on enzyme metabolism using indapamide as an example. A multiplex mass spectrometry method was used to examine the single nucleotide polymorphism (SNP) profile of eight major phases I and II metabolic enzymes in 1,038 Taiwanese subjects. A PG/PK study was conducted in 24 healthy subjects to investigate the possible effects of 28 SNPs on drug biotransformation. Among the genetic profile analyzed, eight SNPs from CYP2A6, CYP2C19, CYP2D6, CYP2E1, CYP3A5, and UGT2B7 showed higher variant frequencies than those previously reported in Caucasians or Africans. For instance, we observed 14.7% frequency of the SNP rs5031016 (I471T) from CYP2A6 in Taiwanese, whereas 0% variation was reported in Caucasians and Africans. The PG/PK study of indapamide demonstrated that the polymorphic SNPs CYP2C9 rs4918758 and CYP2C19 rs4244285 appeared to confer lowered enzyme activity, as indicated by increased C max (25% ∼ 64%), increased area under the plasma level-time curves (30∼76%), increased area under the time infinity (43% ∼ 80%), and lower apparent clearance values than PK for wild-type indapamide. Our results reinforce the biochemical support of CYP2C19 in indapamide metabolism and identify a possible new participating enzyme CYP2C9. The PG/PK approach contributed toward understanding the genetic makeup of different ethnic groups and associations of enzymes in drug metabolism. It could be used to identify two genetic markers that enable to differentiate subjects with varied PK outcomes of indapamide.
KEY WORDSindapamide metabolic enzymes pharmacogenetics pharmacokinetics SNPs
The authors are grateful to Hung-Lun Chiang and Yie-Wen Liao at the Institute of Biomedical Sciences, Academia Sinica, for genotyping analysis. The statistical advices from Mr. Chin Lin at the School of Public Health, National Defense Medical Center, were also appreciated.
Conflict of Interest
The authors declare no conflict of interest.
- 20.Jurinke C, van den Boom D, Cantor C, Köster H. The use of MassARRAY technology for high throughput genotyping chip technology. In: Hoheisel J, Brazma A, Büssow K, Cantor C, Christians F, Chui G, et al. editors. Advances in biochemical engineering/biotechnology. Advances in biochemical engineering/biotechnology, 77. Heidelberg: Springer; 2002. p. 57–74.Google Scholar
- 34.Pedersen RS, Brasch-Andersen C, Sim SC, Bergmann TK, Halling J, Petersen MS, et al. Linkage disequilibrium between the CYP2C19*17 allele and wildtype CYP2C8 and CYP2C9 alleles: identification of CYP2C haplotypes in healthy Nordic populations. Eur J Clin Pharmacol. 2010;66(12):1199–205.CrossRefPubMedGoogle Scholar
- 35.Bohanec Grabar P, Grabnar I, Rozman B, Logar D, Tomsic M, Suput D, et al. Investigation of the influence of CYP1A2 and CYP2C19 genetic polymorphism on 2-cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]-2-butenamide (A77 1726) pharmacokinetics in leflunomide-treated patients with rheumatoid arthritis. Drug Metab Dispos. 2009;37(10):2061–8.CrossRefPubMedGoogle Scholar