Involvement of multidrug resistance protein 4 in the hepatocyte efflux of lamivudine and entecavir.
Mol Med Rep
; 17(5): 7113-7121, 2018 05.
Article
em En
| MEDLINE
| ID: mdl-29568871
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 [wildtype hepatitis B virus (HBV)] and HepG2.A64 (ETVresistant 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 wildtype cells were higher than those in ETVresistant 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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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Contexto em Saúde:
2_ODS3
Problema de saúde:
2_enfermedades_transmissibles
Assunto principal:
Antivirais
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Lamivudina
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Hepatócitos
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Proteínas Associadas à Resistência a Múltiplos Medicamentos
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Guanina
Limite:
Humans
Idioma:
En
Revista:
Mol Med Rep
Ano de publicação:
2018
Tipo de documento:
Article