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Pharmaceutical Research

, 35:14 | Cite as

Indinavir Alters the Pharmacokinetics of Lamivudine Partially via Inhibition of Multidrug and Toxin Extrusion Protein 1 (MATE1)

  • Qing Li
  • Zhi Ye
  • Peng Zhu
  • Dong Guo
  • Hong Yang
  • Jin Huang
  • Wei Zhang
  • James E. Polli
  • Yan ShuEmail author
Research Paper

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.

KEY WORDS

drug-drug interaction indinavir lamivudine multidrug and toxin extrusion protein organic cation transporter 

ABBREVIATIONS

3TC

2′-deoxynucleoside-3′-thiacytidine

ANOVA

Analysis of variance

ASP+

4-(4-(dimethylamino)styryl)-N-methylpyridinium iodide

AUC

The area under the plasma concentration-time curve

BSA

Body surface area

Cmax

Maximum plasma concentration

CYP450

Cytochrome P450

DDIs

Drug-drug interactions

DMEM

Dulbecco’s modified Eagle’s medium

HAART

Highly active antiretroviral therapy

HBV

Hepatitis B virus

HED

Human equivalent dose

HEK-293 cells

Human embryonic kidney 293 cells

HIV

Human immunodeficiency virus

hMATE1

Human multidrug and toxin extrusion protein 1

hOCT2

Human organic cation transporter 2

IACUC

Institutional Animal Care and Use Committee

Ki

Observed inhibitory constant

NIH

National Institutes of Health

NNRTIs

Non-nucleoside reverse transcriptase inhibitors

NRTIs

Nucleoside reverse transcriptase inhibitors

OAT

Organic anion transporters

PBS

Phosphate buffered saline

PIs

Protease inhibitors

SD

Standard deviation

TBC

Total body clearance

T1/2

Half-life

Tmax

The time to maximal plasma concentration

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Clinical PharmacologyXiangya Hospital, Central South UniversityChangshaChina
  2. 2.Department of Pharmaceutical SciencesSchool of Pharmacy, University of Maryland at BaltimoreBaltimoreUSA
  3. 3.Department of AnesthesiologyXiangya Hospital, Central South UniversityChangshaChina

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