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

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)206-213
Number of pages8
JournalAAPS Journal
Volume16
Issue number2
DOIs
Publication statusPublished - Jan 1 2014
Externally publishedYes

Fingerprint

Indapamide
Genetic Polymorphisms
Pharmacokinetics
Single Nucleotide Polymorphism
Enzymes
Pharmacogenetics
Cytochrome P-450 CYP3A
Cytochrome P-450 CYP2E1
Cytochrome P-450 CYP2D6
Biotransformation
Genetic Markers
Ethnic Groups
Pharmaceutical Preparations
Mass Spectrometry
Healthy Volunteers
Population
Cytochrome P-450 CYP2C19

Keywords

  • indapamide
  • metabolic enzymes
  • pharmacogenetics
  • pharmacokinetics
  • SNPs

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

Wang, T. H., Hsiong, C. H., Ho, H. T., Shih, T. Y., Yen, S. J., Wang, H. H., ... Hu, O. Y. P. (2014). Genetic polymorphisms of metabolic enzymes and the pharmacokinetics of indapamide in Taiwanese subjects. AAPS Journal, 16(2), 206-213. https://doi.org/10.1208/s12248-013-9535-x

Genetic polymorphisms of metabolic enzymes and the pharmacokinetics of indapamide in Taiwanese subjects. / Wang, Teng Hsu; Hsiong, Cheng Huei; Ho, Hsin Tien; Shih, Tung Yuan; Yen, San Jan; Wang, Hui Hung; Wu, Jer Yuarn; Kuo, Benjamin Pei Chung; Chen, Yuan Tsong; Ho, Shung Tai; Hu, Oliver Yoa Pu.

In: AAPS Journal, Vol. 16, No. 2, 01.01.2014, p. 206-213.

Research output: Contribution to journalArticle

Wang, TH, Hsiong, CH, Ho, HT, Shih, TY, Yen, SJ, Wang, HH, Wu, JY, Kuo, BPC, Chen, YT, Ho, ST & Hu, OYP 2014, 'Genetic polymorphisms of metabolic enzymes and the pharmacokinetics of indapamide in Taiwanese subjects', AAPS Journal, vol. 16, no. 2, pp. 206-213. https://doi.org/10.1208/s12248-013-9535-x
Wang, Teng Hsu ; Hsiong, Cheng Huei ; Ho, Hsin Tien ; Shih, Tung Yuan ; Yen, San Jan ; Wang, Hui Hung ; Wu, Jer Yuarn ; Kuo, Benjamin Pei Chung ; Chen, Yuan Tsong ; Ho, Shung Tai ; Hu, Oliver Yoa Pu. / Genetic polymorphisms of metabolic enzymes and the pharmacokinetics of indapamide in Taiwanese subjects. In: AAPS Journal. 2014 ; Vol. 16, No. 2. pp. 206-213.
@article{a38ce8a77ec6402db70a06bbeaee30e4,
title = "Genetic polymorphisms of metabolic enzymes and the pharmacokinetics of indapamide in Taiwanese subjects",
abstract = "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.",
keywords = "indapamide, metabolic enzymes, pharmacogenetics, pharmacokinetics, SNPs",
author = "Wang, {Teng Hsu} and Hsiong, {Cheng Huei} and Ho, {Hsin Tien} and Shih, {Tung Yuan} and Yen, {San Jan} and Wang, {Hui Hung} and Wu, {Jer Yuarn} and Kuo, {Benjamin Pei Chung} and Chen, {Yuan Tsong} and Ho, {Shung Tai} and Hu, {Oliver Yoa Pu}",
year = "2014",
month = "1",
day = "1",
doi = "10.1208/s12248-013-9535-x",
language = "English",
volume = "16",
pages = "206--213",
journal = "AAPS Journal",
issn = "1550-7416",
publisher = "Springer New York",
number = "2",

}

TY - JOUR

T1 - Genetic polymorphisms of metabolic enzymes and the pharmacokinetics of indapamide in Taiwanese subjects

AU - Wang, Teng Hsu

AU - Hsiong, Cheng Huei

AU - Ho, Hsin Tien

AU - Shih, Tung Yuan

AU - Yen, San Jan

AU - Wang, Hui Hung

AU - Wu, Jer Yuarn

AU - Kuo, Benjamin Pei Chung

AU - Chen, Yuan Tsong

AU - Ho, Shung Tai

AU - Hu, Oliver Yoa Pu

PY - 2014/1/1

Y1 - 2014/1/1

N2 - 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.

AB - 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.

KW - indapamide

KW - metabolic enzymes

KW - pharmacogenetics

KW - pharmacokinetics

KW - SNPs

UR - http://www.scopus.com/inward/record.url?scp=84895869301&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84895869301&partnerID=8YFLogxK

U2 - 10.1208/s12248-013-9535-x

DO - 10.1208/s12248-013-9535-x

M3 - Article

C2 - 24357089

AN - SCOPUS:84895869301

VL - 16

SP - 206

EP - 213

JO - AAPS Journal

JF - AAPS Journal

SN - 1550-7416

IS - 2

ER -