title: Species-specific interaction of HIV protease inhibitors with accumulation of cholyl-glycylamido-fluorescein (CGamF) in sandwich-cultured hepatocytes.
abstract: Using sandwich-cultured hepatocytes from rat, dog, pig, and human, we investigated the species-specificity of interaction of HIV protease inhibitors (PI) with in vitro hepatic accumulation of the bile salt analogue cholyl-glycylamido-fluorescein (CGamF). Extracellular sodium depletion or coincubation with the OATP/Oatp inhibitors rifampicin and digoxin revealed that about 35% of active CGamF accumulation was mediated by Ntcp/NTCP in rat and human hepatocytes, while the contribution of this sodium-dependent transporter reached 50-60% in dog and pig hepatocytes. One or more sodium-independent transporters, likely belonging to the Oatp/OATP family, constitute a major transport mechanism for CGamF accumulation. Various HIV PI (0.5, 5, 25 microM) exhibited pronounced species differences in their interaction with active CGamF accumulation (1 microM), although some similarity was observed between the dog and human interaction profiles when HIV PI were tested at 0.5 microM. Atazanavir, indinavir, and darunavir were the most potent inhibitors of CGamF accumulation in human hepatocytes. Potent inhibition of CGamF accumulation by ritonavir in rat hepatocytes contrasted with a weak effect in human hepatocytes. Thorough characterization of in vitro disposition of probe substrates in preclinical species compared to human hepatocytes will ultimately support a better insight in species-specific mechanisms underlying drug interactions and drug-mediated toxicity.
authors.affiliation: Laboratory for Pharmacotechnology and Biopharmacy, Department of Pharmaceutical Sciences, Katholieke Universiteit Leuven, O&N2, Herestraat 49-bus-921, 3000 Leuven, Belgium.
authors.forename: Zhi-wei
authors.initials: ZW
authors.lastname: Ye
authors.forename: Jos
authors.initials: J
authors.lastname: Van Pelt
authors.forename: Sandrine
authors.initials: S
authors.lastname: Camus
authors.forename: Jan
authors.initials: J
authors.lastname: Snoeys
authors.forename: Patrick
authors.initials: P
authors.lastname: Augustijns
authors.forename: Pieter
authors.initials: P
authors.lastname: Annaert
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D000069454:Darunavir; D004285:Dogs; D004304:Dosage Forms; D005260:Female; D005452:Fluoresceins; D017320:HIV Protease Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D019469:Indinavir / Q000378:metabolism / Q000494:pharmacology; D008099:Liver / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D051381:Rats; D017208:Rats, Wistar; D019438:Ritonavir / Q000378:metabolism / Q000494:pharmacology; D013045:Species Specificity; D013449:Sulfonamides / Q000378:metabolism / Q000494:pharmacology; D034421:Sus scrofa
chemical_list: D001647:Bile Acids and Salts; D004304:Dosage Forms; D005452:Fluoresceins; D017320:HIV Protease Inhibitors; D013449:Sulfonamides; C090312:cholylglycylamidofluorescein; D019469:Indinavir; D019438:Ritonavir; D000069454:Darunavir