Abstract
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.
Footnotes
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This work was supported in part by a 2003 to 2004 developmental grant from the University of North Carolina at Chapel Hill Center for AIDS Research, by a National Institutes of Health-funded program (9P30 AI 50410-04), and by National Institutes of Health Grants GM41935, CA106101, GM54724, GM31304, and AI54980. M.P.M. is the recipient of an American Foundation for Pharmaceutical Education predoctoral fellowship.
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A portion of this work was previously presented: McRae MP, Brouwer KLR, and Kashuba ADM (2004) Effects of ritonavir and nevirapine on hepatic transport and biliary excretion index of taurocholate in sandwich-cultured primary human and rat hepatocytes. International Society for the Study of Xenobiotics Annual Meeting; 2004 Aug 29–Sept 2; Vancouver, BC, Canada. pp 475, International Society for the Study of Xenobiotics, Washington, DC; and McRae MP, Bourdet DL, Kim RB, Brouwer KLR, and Kashuba ADM (2004) The antiretrovirals ritonavir, saquinavir and efavirenz, but not nevirapine, inhibit taurocholate uptake in NTCP-injected oocytes, PT2337. American Association of Pharmaceutical Scientists Annual Meeting; 2004 Nov 7–11; Baltimore, MD. American Association of Pharmaceutical Scientists, Arlington, VA.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.102657.
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ABBREVIATIONS: BSEP, bile salt export pump; DMEM, Dulbecco's modified Eagle's medium; FBS, fetal bovine serum; GFP, green fluorescence protein; HBSS, Hanks' balanced salt solution; BEI, biliary excretion index; NTCP, sodium-dependent taurocholate-cotransporting polypeptide; OATP, organic anion-transporting polypeptide.
- Received February 24, 2006.
- Accepted May 22, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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Ritonavir, Saquinavir, and Efavirenz, but Not Nevirapine, Inhibit Bile Acid Transport in Human and Rat Hepatocytes
