title: More relevant prediction for in vivo drug interaction of candesartan cilexetil on hepatic bile acid transporter BSEP using sandwich-cultured hepatocytes.
abstract: Bile salt export pump (BSEP) plays a major role in biliary secretion of bile salts; therefore, drug-induced cholestasis could occur because of BSEP inhibition by drugs. Drug interaction on hepatic bile canalicular transporters such as BSEP with prodrugs that are rapidly metabolized has not been evaluated well. In the present study, candesartan cilexetil (CIL) was used as a model compound and its inhibitory potential against BSEP was determined in sandwich-cultured human hepatocytes (hSCH) as well as in BSEP-expressing membrane vesicles. CIL exhibited potent BSEP inhibition with an IC50 value of 6.2 µM in the transport assay using membrane vesicles. In contrast, BSEP inhibition by CIL was not observed in hSCH after 120 min exposure. This discordance is possibly explained by metabolic elimination of CIL in hSCH because BSEP inhibition became reversely pronounced under the conditions where CIL metabolism was suppressed by diisopropyl fluorophosphates. The results observed in hSCH are consistent with the fact that liver dysfunction or jaundice occurs with low frequency in clinical use of CIL, which may not be obtained by membrane vesicle study on the effect of CIL on BSEP.
authors.affiliation: Department of Membrane Transport and Biopharmaceutics, Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University.
authors.forename: Hajime
authors.initials: H
authors.lastname: Fukuda
authors.forename: Takeo
authors.initials: T
authors.lastname: Nakanishi
authors.forename: Ikumi
authors.initials: I
authors.lastname: Tamai
mesh_terms: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001562:Benzimidazoles / Q000378:metabolism / Q000493:pharmacokinetics*; D001713:Biphenyl Compounds / Q000493:pharmacokinetics*; D002478:Cells, Cultured; D002779:Cholestasis / Q000378:metabolism; D004347:Drug Interactions; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D011355:Prodrugs / Q000493:pharmacokinetics*; D013777:Tetrazoles / Q000378:metabolism / Q000493:pharmacokinetics*; D046509:Tissue Culture Techniques
chemical_list: C093491:ABCB11 protein, human; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D011355:Prodrugs; D013777:Tetrazoles; C077793:candesartan cilexetil; C081643:candesartan