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Repaglinide-irbesartan drug interaction: effects of SLCO1B1 polymorphism on repaglinide pharmacokinetics and pharmacodynamics in Chinese population

  • Pharmacogenetics
  • Published:
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Abstract

Purpose

On account of the potential inhibition of OATP1B1 (organic anion transporting polypeptide) by angiotensin II receptor blockers (ARBs) and the effects of SLCO1B1 (solute carrier organic anion transporter family member) polymorphism, the aim of current study is to assess the impact of ARBs on the pharmacokinetics (PK) and pharmacodynamics (PD) of repaglinide in Chinese healthy volunteers with different SLCO1B1 genotypes.

Methods

The in vitro study was conducted on irbesartan, valsartan, olmesartan, and losartan by using HEK293 cells transfected with OATP1B1. Data on drug interactions between repaglinide and irbesartan from 21 healthy Chinese-Han male volunteers were collected and analyzed.

Results

IC50 from in vitro study suggested irbesartan was the most potent inhibitor of OATP1B1 transporter. Clinical data from single dose of repaglinide indicated SLCO1B1 c.521 T>C polymorphism influenced the PK and PD of repaglinide in healthy Chinese-Han male volunteers. In subjects with SLCO1B1 c.521 TT genotype, irbesartan comedication increased the exposure of repaglinide. In details, the peak plasma concentration [Cmax] increased 84% (P = 0.003) and the area under the curve of plasma concentration 0–8 h [AUC0–8] increased 34% (P = 0.004), while the minimum blood glucose concentration [Cmin] decreased 33.8% (P = 0.005). No significant change was observed in repaglinide exposure in subjects with SLCO1B1 c.521 TC genotype in presence or absence of irbesartan.

Conclusion

SLCO1B1 c.521 T>C polymorphism affects the PK of repaglinide in Chinese population. Irbesartan increased repaglinide exposure in subjects with SLCO1B1 c.521 TT genotype, but not SLCO1B1 c.521 TC genotype.

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Funding

This work was supported by the National Natural Science Foundation of China (81373490, 81573463, 81573508), National Key Research and Development Programs (2016YFC1306900, 2016YFC0905002, 2016YFC1201805), The Strategy-Oriented Special Project of Central South University in China (ZLXD2017003), and Hunan Natural Science Foundation (2017JJ3464).

Author information

Author notes

  1. Qi Pei and Jun-Yan Liu contributed equally to this work.

Authors and Affiliations

  1. Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China

    Qi Pei, Ji-Ye Yin, Yi Zheng, Pan Xie, Hong-Hao Zhou, Xi Li & Zhao-Qian Liu

  2. Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, 410078, People’s Republic of China

    Qi Pei, Ji-Ye Yin, Yi Zheng, Pan Xie, Hong-Hao Zhou, Xi Li & Zhao-Qian Liu

  3. Department of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, People’s Republic of China

    Qi Pei, Guo-Ping Yang, Shi-Kun Liu, Cheng-Xian Guo & Mi Luo

  4. Xiangya School of Medicine, Central South University, Changsha, 410078, Hunan, People’s Republic of China

    Jun-Yan Liu

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  1. Qi Pei
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Contributions

Zhao-QianLiu, Guo-Ping Yang, and Qi Pei conceived and designed the experiments; Qi Pei, Yi Zheng, Jun-Yan Liu, and Mi Luo analyzed the plasma concentrations. Qi Pei, Cheng-Xian Guo, Jun-Yan Liu, and Ji-Ye Yin performed the in vitro research. Qi Pei and Xi Li analyzed the data. Qi Pei, Xi Li, Ji-Ye Yin, and Zhao-Qian Liu wrote the paper. Shi-Kun Liu, Pan Xie, and Hong-Hao Zhou reviewed and edited the manuscript. All authors have read and approved the manuscript.

Corresponding authors

Correspondence to Xi Li or Zhao-Qian Liu.

Ethics declarations

The study protocol was reviewed and approved by the ethics committee of the Institute of Clinical Pharmacology, Central South University (Changsha, Hunan, P. R. China).

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Pei, Q., Liu, JY., Yin, JY. et al. Repaglinide-irbesartan drug interaction: effects of SLCO1B1 polymorphism on repaglinide pharmacokinetics and pharmacodynamics in Chinese population. Eur J Clin Pharmacol 74, 1021–1028 (2018). https://doi.org/10.1007/s00228-018-2477-6

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  • DOI: https://doi.org/10.1007/s00228-018-2477-6

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