Use of cassette dosing in sandwich-cultured rat and human hepatocytes to identify drugs that inhibit bile acid transport.
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.
Wolf
Kristina K
KK
Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Vora
Sapana
S
Webster
Lindsey O
LO
Generaux
Grant T
GT
Polli
Joseph W
JW
Brouwer
Kim L R
KL
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
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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