Indinavir Alters the Pharmacokinetics of Lamivudine Partially via Inhibition of Multidrug and Toxin Extrusion Protein 1 (MATE1)
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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.
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.
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.
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.
KEY WORDSdrug-drug interaction indinavir lamivudine multidrug and toxin extrusion protein organic cation transporter
Analysis of variance
The area under the plasma concentration-time curve
Body surface area
Maximum plasma concentration
Dulbecco’s modified Eagle’s medium
Highly active antiretroviral therapy
Hepatitis B virus
Human equivalent dose
- HEK-293 cells
Human embryonic kidney 293 cells
Human immunodeficiency virus
Human multidrug and toxin extrusion protein 1
Human organic cation transporter 2
Institutional Animal Care and Use Committee
Observed inhibitory constant
National Institutes of Health
Non-nucleoside reverse transcriptase inhibitors
Nucleoside reverse transcriptase inhibitors
Organic anion transporters
Phosphate buffered saline
Total body clearance
The time to maximal plasma concentration
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