Ritonavir, saquinavir, and efavirenz, but not nevirapine, inhibit bile acid transport in human and rat hepatocytes.

McRae MP, Lowe CM, Tian X, Bourdet DL, Ho RH, Leake BF, Kim RB, Brouwer KL, Kashuba AD
J Pharmacol Exp Ther. 2006 318 (3): 1068-75

PMID: 16720753 · DOI:10.1124/jpet.106.102657

Human immunodeficiency virus-infected patients on antiretroviral drug therapy frequently experience hepatotoxicity, the underlying mechanism of which is poorly understood. Hepatotoxicity from other compounds such as bosentan and troglitazone has been attributed, in part, to inhibition of hepatocyte bile acid excretion. This work tested the hypothesis that antiretroviral drugs modulate hepatic bile acid transport. Ritonavir (28 microM), saquinavir (15 microM), and efavirenz (32 microM) inhibited [(3)H]taurocholate transport in bile salt export pump expressing Sf9-derived membrane vesicles by 90, 71, and 33%, respectively. In sandwich-cultured human hepatocytes, the biliary excretion index (BEI) of [(3)H]taurocholate was maximally decreased 59% by ritonavir, 39% by saquinavir, and 20% by efavirenz. Likewise, in sandwich-cultured rat hepatocytes, the BEI of [(3)H]taurocholate was decreased 100% by ritonavir and 94% by saquinavir. Sodium-dependent and -independent initial uptake rates of [(3)H]taurocholate in suspended rat hepatocytes were significantly decreased by ritonavir, saquinavir, and efavirenz. [(3)H]Taurocholate transport by recombinant NTCP and Ntcp was inhibited by ritonavir (IC(50) = 2.1 and 6.4 microM in human and rat, respectively), saquinavir (IC(50) = 6.7 and 20 microM, respectively), and efavirenz (IC(50) = 43 and 97 microM, respectively). Nevirapine (75 microM) had no effect on bile acid transport in any model system. In conclusion, ritonavir, saquinavir, and efavirenz, but not nevirapine, inhibited both the hepatic uptake and biliary excretion of taurocholate.

MeSH Terms (27)

Adolescent Adult Aged Aged, 80 and over Alkynes Animals Anti-HIV Agents ATP-Binding Cassette Transporters ATP Binding Cassette Transporter, Subfamily B, Member 11 Benzoxazines Biological Transport Cells, Cultured Child Cyclopropanes Hepatocytes Humans Male Middle Aged Nevirapine Organic Anion Transporters Organic Anion Transporters, Sodium-Dependent Oxazines Rats Ritonavir Saquinavir Symporters Taurocholic Acid

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