@article {Griffin188, author = {LaToya M. Griffin and Paul B. Watkins and Cassandra H. Perry and Robert L. St. Claire III and Kim L. R. Brouwer}, title = {Combination Lopinavir and Ritonavir Alter Exogenous and Endogenous Bile Acid Disposition in Sandwich-Cultured Rat Hepatocytes}, volume = {41}, number = {1}, pages = {188--196}, year = {2013}, doi = {10.1124/dmd.112.047225}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Inhibition of the bile salt export pump (BSEP) can cause intracellular accumulation of bile acids and is a risk factor for drug-induced liver injury in humans. Antiretroviral protease inhibitors lopinavir (LPV) and ritonavir (RTV) are reported BSEP inhibitors. However, the consequences of LPV and RTV, alone and combined (LPV/r), on hepatocyte viability, bile acid transport, and endogenous bile acid disposition in rat hepatocytes have not been examined. The effect of LPV, RTV, and LPV/r on cellular viability and the disposition of [3H]taurocholic acid (TCA) and [14C]chenodeoxycholic acid (CDCA) was determined in sandwich-cultured rat hepatocytes (SCRH) and suspended rat hepatocytes. Lactate dehydrogenase and ATP assays revealed a concentration-dependent effect of LPV and RTV on cellular viability. LPV (5 {\textmu}M), alone and combined with 5 {\textmu}M RTV, significantly decreased [3H]TCA accumulation in cells + bile of SCRHs compared with control. LPV/r significantly increased [3H]TCA cellular accumulation (7.7 {\textpm} 0.1 pmol/mg of protein) compared with vehicle and 5 {\textmu}M LPV alone (5.1 {\textpm} 0.7 and 5.0 {\textpm} 0.5 pmol/mg of protein). The [3H]TCA biliary clearance was reduced significantly by LPV and RTV and further reduced by LPV/r. LPV and RTV did not affect the initial uptake rates of [3H]TCA or [14C]CDCA in suspended rat hepatocytes. LPV (50 {\textmu}M), RTV (5 {\textmu}M), and LPV/r (5 and 50 {\textmu}M/5 {\textmu}M) significantly decreased the accumulation of total measured endogenous bile acids (TCA, glycocholic acid, taurochenodeoxycholic acid, glycochenodeoxycholic acid, and α/β-tauromuricholic acid) in SCRH. Quantification of endogenous bile acids in SCRH may reveal important adaptive responses associated with exposure to known BSEP inhibitors.}, issn = {0090-9556}, URL = {https://dmd.aspetjournals.org/content/41/1/188}, eprint = {https://dmd.aspetjournals.org/content/41/1/188.full.pdf}, journal = {Drug Metabolism and Disposition} }