Abstract
Entecavir (ETV) is one of the most potent agents for the treatment of the hepatitis B viral infection. The drug is principally eliminated by the kidney. The goal of this study was to investigate the potential of ETV to interact in vitro with the renal SLC transporters hOAT1, hOCT2, hCNT2 and hCNT3. Potential drug–drug interactions of ETV at the renal transporters with antiviral drugs known to be excreted by the kidney (adefovir, tenofovir, cidofovir) as well as transporter-dependent cytotoxicity were also examined. Interactions with the selected transporters along with cytotoxicity were studied in several transiently transfected cellular models using specific substrates and inhibitors. ETV was found to be both a substrate and inhibitor of hOAT1 (IC50 = 175.3 μM), hCNT2 (IC50 = 241.9 μM) and hCNT3 (IC50 = 278.4 μM) transporters, although it interacted with the transporters with relatively low affinities. ETV inhibited the cellular uptake of adefovir, tenofovir, and cidofovir by hOAT1; however, effective inhibition was shown at ETV concentrations exceeding therapeutic levels. In comparison with adefovir, tenofovir, and cidofovir, ETV displayed no transporter-mediated cytotoxicity in cells transfected with hOAT1, hCNT2, and hCNT3. No significant interaction of ETV with hOCT2 was detected. The study demonstrates interactions of ETV with several human renal transporters. For the first time, an interaction of ETV with the hCNTs was proved. We show that the potency of ETV to cause nephrotoxicity and/or clinically significant drug-drug interactions related to the tested transporters is considerably lower than that of adefovir, tenofovir, and cidofovir.
Highlights
Entecavir (ETV), a synthetic guanosine analog, is one of the most potent and highly selective agents for the treatment of chronic hepatitis B (HBV) infection
This work builds on an in vivo study which suggested an involvement of organic anion and cation transporters in the renal excretion of ETV (Yanxiao et al, 2011)
The authors of this study have demonstrated that both probenecid and cimetidine show an inhibitory effect on the renal excretion of ETV after intravenous coadministration
Summary
Entecavir (ETV), a synthetic guanosine analog, is one of the most potent and highly selective agents for the treatment of chronic hepatitis B (HBV) infection. Combinations of ETV and other anti-HBV drugs such as adefovir or tenofovir have been demonstrated to be effective in patients with some types of resistance to antiviral therapy (Sheng et al, 2011; Chae et al, 2012). The solute carrier family (SLC) of membrane transporters located in the renal proximal tubular cells have been shown to interact with numerous widely used antivirals (Cihlar et al, 2009; Minuesa et al, 2011). The most abundantly expressed types of OATs and OCTs in human renal tubular cells are human organic anion transporter 1 (hOAT1) and human organic cation transporter 2 (hOCT2), respectively (Klaassen and Aleksunes, 2010). Several guanosine antivirals show substrate specificity to the OAT and OCT families (Minuesa et al, 2011). Antiviral agents from the group of acyclic nucleoside phosphonates such as adefovir, tenofovir, and cidofovir have been characterized as substrates of hOATs (Uwai et al, 2007)
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