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METABOLISM, TRANSPORT, AND PHARMACOGENOMICS

Ritonavir, Saquinavir, and Efavirenz, but Not Nevirapine, Inhibit Bile Acid Transport in Human and Rat Hepatocytes

School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina (M.P.M., C.M.L., X.T., D.L.B., K.L.R.B., A.D.M.K.); and Division of Clinical Pharmacology, Vanderbilt University, Nashville, Tennessee (R.H.H., B.F.L., R.B.K.)

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 µM), saquinavir (15 µM), and efavirenz (32 µM) inhibited [³H]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 [³H]taurocholate was maximally decreased 59% by ritonavir, 39% by saquinavir, and 20% by efavirenz. Likewise, in sandwich-cultured rat hepatocytes, the BEI of [³H]taurocholate was decreased 100% by ritonavir and 94% by saquinavir. Sodium-dependent and -independent initial uptake rates of [³H]taurocholate in suspended rat hepatocytes were significantly decreased by ritonavir, saquinavir, and efavirenz. [³H]Taurocholate transport by recombinant NTCP and Ntcp was inhibited by ritonavir (IC₅₀ = 2.1 and 6.4 µM in human and rat, respectively), saquinavir (IC₅₀ = 6.7 and 20 µM, respectively), and efavirenz (IC₅₀ = 43 and 97 µM, respectively). Nevirapine (75 µM) 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.

Address correspondence to: Dr. Angela Kashuba, 3318 Kerr Hall, CB 7360, University of North Carolina, Chapel Hill, NC 27599-7360. E-mail: akashuba{at}unc.edu

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