title: Use of cassette dosing in sandwich-cultured rat and human hepatocytes to identify drugs that inhibit bile acid transport.
abstract: Hepatocellular accumulation of bile acids due to inhibition of the canalicular bile salt export pump (BSEP/ABCB11) is one proposed mechanism of drug-induced liver injury (DILI). Some hepatotoxic compounds also are potent inhibitors of bile acid uptake by Na(+)-dependent taurocholate cotransporting polypeptide (NTCP/SLC10A1). This study used a cassette dosing approach in rat and human sandwich-cultured hepatocytes (SCH) to determine whether known or suspected hepatotoxic drugs inhibit bile acid transport individually or in combination. [(3)H]-Taurocholate served as the NTCP/BSEP probe substrate. Individually, cyclosporin A and rifampin decreased taurocholate in vitro biliary clearance (Cl(biliary)) and biliary excretion index (BEI) by more than 20% in rat SCH, suggesting that these drugs primarily inhibited canalicular efflux. In contrast, ampicillin, carbenicillin, cloxacillin, nafcillin, oxacillin, carbamazepine, pioglitazone, and troglitazone decreased the in vitro Cl(biliary) by more than 20% with no notable change in BEI, suggesting that these drugs primarily inhibited taurocholate uptake. Cassette dosing (n=2-4 compounds per cassette) in rat SCH yielded similar findings, and results in human SCH were consistent with rat SCH. In summary, cassette dosing in SCH is a useful in vitro approach to identify compounds that inhibit the hepatic uptake and/or excretion of bile acids, which may cause DILI.
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Kristina K
authors.initials: KK
authors.lastname: Wolf
authors.forename: Sapana
authors.initials: S
authors.lastname: Vora
authors.forename: Lindsey O
authors.initials: LO
authors.lastname: Webster
authors.forename: Grant T
authors.initials: GT
authors.lastname: Generaux
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Polli
authors.forename: Kim L R
authors.initials: KL
authors.lastname: Brouwer
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology; D001646:Bile / Q000378:metabolism; D001647:Bile Acids and Salts / Q000378:metabolism*; D001693:Biological Transport, Active / Q000187:drug effects; D002478:Cells, Cultured; D002756:Cholagogues and Choleretics / Q000494:pharmacology*; D016572:Cyclosporine / Q000494:pharmacology; D003627:Data Interpretation, Statistical; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008099:Liver / Q000378:metabolism; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013656:Taurocholic Acid / Q000378:metabolism
chemical_list: D000890:Anti-Infective Agents; D001647:Bile Acids and Salts; D002756:Cholagogues and Choleretics; D007004:Hypoglycemic Agents; D007166:Immunosuppressive Agents; D013656:Taurocholic Acid; D016572:Cyclosporine
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