Involvement of multidrug resistance protein 4 in the hepatocyte efflux of lamivudine and entecavir

Liu,Yu‑Tian; Liu,Wei; Zhu,Gang‑Yan; Wang,Fu‑Liang; Chen,Qian

doi:10.3892/mmr.2018.8779

Involvement of multidrug resistance protein 4 in the hepatocyte efflux of lamivudine and entecavir

Authors:
- Yu‑Tian Liu
- Wei Liu
- Gang‑Yan Zhu
- Fu‑Liang Wang
- Qian Chen
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Affiliations: Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China, Department of Geriatrics, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China, Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
Published online on: March 19, 2018 https://doi.org/10.3892/mmr.2018.8779
Pages: 7113-7121
Copyright: © Liu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Multidrug resistance protein 4 (MRP4) is capable of transporting acyclic nucleotide phosphonates, but little is known about its role in lamivudine (LAM) and entecavir (ETV) transport. In the present study, the involvement of MRP4 in the transport of LAM and ETV was investigated through in vitro experiments. The cytotoxicity of three antiviral drugs and their activities against HBV as characterized in HepG2.4D14 [wild‑type hepatitis B virus (HBV)] and HepG2.A64 (ETV‑resistant HBV) cells. LAM, ETV and tenofovir (TFV) demonstrated a 50% effective concentration against HBV of 4.14±0.03, 0.13±0.02 and 3.24±0.01 µM in HepG2.4D14 cells and of 5.94±0.20, 6.28±0.07 and 11.43±0.09 µM in HepG2.A64 cells, respectively. After administering 3-([(3-(2-[7-chloro-2-quinolinyl]ethyl)phenyl]-[(3-dimethylamino-3-oxoporphyl)-thio)-methyl]-thio) propanoic acid (MK571), the intracellular concentrations of all three drugs were much lower than the extracellular drug concentrations in these two cell types, whereas the intracellular drug concentrations in wild‑type cells were higher than those in ETV‑resistant cells. Furthermore, the intracellular levels of LAM, ETV and TFV were enhanced and the extracellular concentrations were reduced by addition of MK571. Thus, MRP4 is mainly responsible for the efflux of LAM and ETV in hepatocyte cultures. These results may contribute to enhancing antiviral efficacy.

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