Genetic polymorphisms of metabolic enzymes and the pharmacokinetics of indapamide in Taiwanese subjects

Teng Hsu Wang, Cheng Huei Hsiong, Hsin Tien Ho, Tung Yuan Shih, San Jan Yen, Hui Hung Wang, Jer Yuarn Wu, Benjamin Pei Chung Kuo, Yuan Tsong Chen, Shung Tai Ho, Oliver Yoa Pu Hu

研究成果: 雜誌貢獻文章同行評審

3 引文 斯高帕斯(Scopus)

摘要

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.
原文英語
頁(從 - 到)206-213
頁數8
期刊AAPS Journal
16
發行號2
DOIs
出版狀態已發佈 - 一月 1 2014
對外發佈

ASJC Scopus subject areas

  • 藥學科學

指紋

深入研究「Genetic polymorphisms of metabolic enzymes and the pharmacokinetics of indapamide in Taiwanese subjects」主題。共同形成了獨特的指紋。

引用此