Qi Pei1,2,3, Jun-Yan Liu4, Ji-Ye Yin1,2, Guo-Ping Yang3, Shi-Kun Liu3, Yi Zheng1,2, Pan Xie1,2, Cheng-Xian Guo3, Mi Luo3, Hong-Hao Zhou1,2, Xi Li5,6, Zhao-Qian Liu7,8. 1. Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China. 2. Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, 410078, People's Republic of China. 3. Department of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, People's Republic of China. 4. Xiangya School of Medicine, Central South University, Changsha, 410078, Hunan, People's Republic of China. 5. Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China. lixi6931430@126.com. 6. Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, 410078, People's Republic of China. lixi6931430@126.com. 7. Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China. liuzhaoqian63@126.com. 8. Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, 410078, People's Republic of China. liuzhaoqian63@126.com.
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.
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.
Entities:
Keywords:
Drug interactions; Irbesartan; Pharmacodynamics; Pharmacokinetics; Polymorphism; Repaglinide; SLCO1B1
Authors: Julia Kirchheiner; Ivar Roots; Mark Goldammer; Bernd Rosenkranz; Jürgen Brockmöller Journal: Clin Pharmacokinet Date: 2005 Impact factor: 6.447
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