Qing Li1,2, Zhi Ye2,3, Peng Zhu1, Dong Guo2, Hong Yang2, Jin Huang1, Wei Zhang1, James E Polli2, Yan Shu4,5. 1. Department of Clinical Pharmacology, Xiangya Hospital, Central South University, 110 Xiangya Road, Changsha, 410078, China. 2. Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, 20 N Pine Street, PH N519, Baltimore, 21201, Maryland, USA. 3. Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, 410078, China. 4. Department of Clinical Pharmacology, Xiangya Hospital, Central South University, 110 Xiangya Road, Changsha, 410078, China. yshu@rx.umaryland.edu. 5. Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, 20 N Pine Street, PH N519, Baltimore, 21201, Maryland, USA. yshu@rx.umaryland.edu.
Abstract
PURPOSE: Lamivudine, a characterized substrate for human multidrug and toxin extrusion protein 1 (hMATE1) in vitro, was commonly used with indinavir as a therapy against human immunodeficiency virus (HIV). We aimed to investigate whether mouse MATE1 is involved in the disposition of lamivudine in vivo, and whether there is any transporter-mediated interaction between indinavir and lamivudine. METHODS: The role of MATE1 in the disposition of lamivudine was determined using Mate1 wild type (+/+) and knockout (-/-) mice. The inhibitory potencies of indinavir on lamivudine uptake mediated by OCT2 and MATE1 were determined in human embryonic kidney 293 (HEK 293) cells stably expressing these transporters. The role of MATE1 in the interaction between indinavir and lamivudine in vivo was determined using Mate1 (+/+) and Mate1 (-/-) mice. RESULTS: The plasma concentrations and tissue accumulation of lamivudine were markedly elevated in Mate1 (-/-) mice as compared to those in Mate1 (+/+) mice. Indinavir significantly increased the pharmacokinetic exposure of lamivudine in mice; however, the effect by indinavir was significantly less pronounced in Mate1 (-/-) mice as compared to Mate1(+/+) mice. CONCLUSION: MATE1 played an important role in lamivudine pharmacokinetics. Indinavir could cause drug-drug interaction with lamivudine in vivo via inhibition of MATE1 and additional mechanism.
PURPOSE:Lamivudine, a characterized substrate for humanmultidrug and toxin extrusion protein 1 (hMATE1) in vitro, was commonly used with indinavir as a therapy against human immunodeficiency virus (HIV). We aimed to investigate whether mouseMATE1 is involved in the disposition of lamivudine in vivo, and whether there is any transporter-mediated interaction between indinavir and lamivudine. METHODS: The role of MATE1 in the disposition of lamivudine was determined using Mate1 wild type (+/+) and knockout (-/-) mice. The inhibitory potencies of indinavir on lamivudine uptake mediated by OCT2 and MATE1 were determined in humanembryonic kidney 293 (HEK 293) cells stably expressing these transporters. The role of MATE1 in the interaction between indinavir and lamivudine in vivo was determined using Mate1 (+/+) and Mate1 (-/-) mice. RESULTS: The plasma concentrations and tissue accumulation of lamivudine were markedly elevated in Mate1 (-/-) mice as compared to those in Mate1 (+/+) mice. Indinavir significantly increased the pharmacokinetic exposure of lamivudine in mice; however, the effect by indinavir was significantly less pronounced in Mate1 (-/-) mice as compared to Mate1(+/+) mice. CONCLUSION:MATE1 played an important role in lamivudine pharmacokinetics. Indinavir could cause drug-drug interaction with lamivudine in vivo via inhibition of MATE1 and additional mechanism.
Authors: Muhammad Daniyal; Muhammad Akram; Abdul Hamid; Allah Nawaz; Khan Usmanghani; Saeed Ahmed; Leena Hameed Journal: Pak J Pharm Sci Date: 2016-07 Impact factor: 0.684
Authors: Robert S Brown; Brian J McMahon; Anna S F Lok; John B Wong; Ahmed T Ahmed; Mohamed A Mouchli; Zhen Wang; Larry J Prokop; Mohammad Hassan Murad; Khaled Mohammed Journal: Hepatology Date: 2015-11-13 Impact factor: 17.425