Biopharmaceutics & Drug Disposition vol:31 issue:2-3 pages:178-188
Hepatotoxicity has been reported as side-effect in some patients on HIV protease inhibitors (PI). Since transporter interaction has been implicated as a mechanism underlying drug-mediated hepatotoxicity and drug-drug interactions, we studied interaction of PI with the hepatic canalicular efflux transporter ABCC2 (MRP2; Multidrug Resistance Associated Protein-2). Interaction with ABCC2/Abcc2 was evaluated in human and rat sandwich-cultured hepatocytes using 5(6)-carboxy-2',7'-dichlorofluorescein (CDF) as substrate. In rat hepatocytes, interaction with estradiol-17-β-D-glucuronide (E17G) efflux was also studied. In human hepatocytes, saquinavir, ritonavir and atazanavir were the most efficient inhibitors of ABCC2-mediated biliary excretion of CDF, whereas in rat hepatocytes indinavir, lopinavir and nelfinavir were most efficient. No species-similarity was found for ABCC2/Abcc2 inhibition. In rat hepatocytes, the effects on Abcc2 were substrate-dependent as inhibition of biliary excretion of E17G was most pronounced for saquinavir (completely blocked), amprenavir (82% inhibition) and indinavir (68% inhibition). In conclusion, several HIV PI show substantial ABCC2 inhibition, which, combined with effects of PI on other hepatobiliary disposition mechanisms, will determine the clinical relevance of these in vitro interaction data.