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Genetic Polymorphisms of Metabolic Enzymes and the Pharmacokinetics of Indapamide in Taiwanese Subjects

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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.

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ACKNOWLEDGMENTS

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.

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Authors and Affiliations

  1. School of Pharmacy, National Defense Medical Center, P.O. Box 90048-512, Taipei, Taiwan, Republic of China

    Teng-Hsu Wang, Cheng-Huei Hsiong, Tung-Yuan Shih, San-Jan Yen & Oliver Yoa-Pu Hu

  2. Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, Republic of China

    Hui-Hung Wang, Jer-Yuarn Wu & Yuan-Tsong Chen

  3. Department of Medical Research, China Medical College Hospital, Taichung, Taiwan, Republic of China

    Jer-Yuarn Wu

  4. Mithra Bioindustry Co., LTD, Taipei, Taiwan, Republic of China

    Benjamin Pei-Chung Kuo

  5. Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, 27710, USA

    Yuan-Tsong Chen

  6. Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, Republic of China

    Hsin-Tien Ho

  7. Department of Anesthesiology, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China

    Shung-Tai Ho

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  1. Teng-Hsu Wang
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  2. Cheng-Huei Hsiong
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  11. Oliver Yoa-Pu Hu
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Correspondence to Oliver Yoa-Pu Hu.

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Wang, TH., Hsiong, CH., Ho, HT. et al. Genetic Polymorphisms of Metabolic Enzymes and the Pharmacokinetics of Indapamide in Taiwanese Subjects. AAPS J 16, 206–213 (2014). https://doi.org/10.1208/s12248-013-9535-x

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  • DOI: https://doi.org/10.1208/s12248-013-9535-x

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