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Ritonavir, saquinavir, and efavirenz, but not nevirapine, inhibit bile acid transport in human and rat hepatocytes
- Source :
- The Journal of pharmacology and experimental therapeutics. 318(3)
- Publication Year :
- 2006
-
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 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.
- Subjects :
- Adult
Cyclopropanes
Male
Taurocholic Acid
Efavirenz
Nevirapine
Organic anion transporter 1
Adolescent
Anti-HIV Agents
viruses
Organic Anion Transporters
Organic Anion Transporters, Sodium-Dependent
Pharmacology
chemistry.chemical_compound
immune system diseases
Oxazines
medicine
Animals
Humans
Child
ATP Binding Cassette Transporter, Subfamily B, Member 11
Cells, Cultured
Saquinavir
Aged
Aged, 80 and over
Ritonavir
biology
Symporters
virus diseases
Troglitazone
Biological Transport
biochemical phenomena, metabolism, and nutrition
Middle Aged
Bile Salt Export Pump
Benzoxazines
Rats
medicine.anatomical_structure
chemistry
Hepatocyte
Alkynes
biology.protein
Hepatocytes
Molecular Medicine
ATP-Binding Cassette Transporters
medicine.drug
Subjects
Details
- ISSN :
- 00223565
- Volume :
- 318
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- The Journal of pharmacology and experimental therapeutics
- Accession number :
- edsair.doi.dedup.....c6a6a6854946ae442339adefc381ed10