title: Utility of bilirubins and bile acids as endogenous biomarkers for the inhibition of hepatic transporters.
abstract: It is useful to identify endogenous substrates for the evaluation of drug-drug interactions via transporters. In this study, we investigated the utility of bilirubins, substrates of OATPs and MRP2, and bile acids and substrates of NTCP and BSEP, as biomarkers for the inhibition of transporters. In rats administered 20 and 80 mg/kg rifampicin, the plasma levels of bilirubin glucuronides were elevated, gradually decreased, and almost returned to the baseline level at 24 hours after administration without an elevation of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). This result indicates the transient inhibition of rOatps and/or rMrp2. Although the correlation between free plasma concentrations and IC50 values of rOatps depended on the substrates used in the in vitro studies, the inhibition of rOatps by rifampicin was confirmed in the in vivo study using valsartan as a substrate of rOatps. In rats administered 10 and 30 mg/kg cyclosporin A, the plasma levels of bile acids were elevated and persisted for up to 24 hours after administration without an elevation of ALT and AST. This result indicates the continuous inhibition of rNtcp and/or rBsep, although there were differences between the free plasma or liver concentrations and IC50 values of rNtcp or rBsep, respectively. This study suggests that the monitoring of bilirubins and bile acids in plasma is useful in evaluating the inhibitory potential of their corresponding transporters.
authors.affiliation: DMPK Research Laboratory, Research Division, Mitsubishi Tanabe Pharma Corporation, Saitama, Japan (T.W., M.K., Ta.S., R.O.); and Safety Research Laboratory, Research Division, Mitsubishi Tanabe Pharma Corporation, Chiba, Japan (M.M., To.S., N.M.) Watanabe.Tomoko@mc.mt-pharma.co.jp.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: DMPK Research Laboratory, Research Division, Mitsubishi Tanabe Pharma Corporation, Saitama, Japan (T.W., M.K., Ta.S., R.O.); and Safety Research Laboratory, Research Division, Mitsubishi Tanabe Pharma Corporation, Chiba, Japan (M.M., To.S., N.M.).
authors.forename: Manami
authors.initials: M
authors.lastname: Miyake
authors.affiliation: DMPK Research Laboratory, Research Division, Mitsubishi Tanabe Pharma Corporation, Saitama, Japan (T.W., M.K., Ta.S., R.O.); and Safety Research Laboratory, Research Division, Mitsubishi Tanabe Pharma Corporation, Chiba, Japan (M.M., To.S., N.M.).
authors.forename: Toshinobu
authors.initials: T
authors.lastname: Shimizu
authors.affiliation: DMPK Research Laboratory, Research Division, Mitsubishi Tanabe Pharma Corporation, Saitama, Japan (T.W., M.K., Ta.S., R.O.); and Safety Research Laboratory, Research Division, Mitsubishi Tanabe Pharma Corporation, Chiba, Japan (M.M., To.S., N.M.).
authors.forename: Miho
authors.initials: M
authors.lastname: Kamezawa
authors.affiliation: DMPK Research Laboratory, Research Division, Mitsubishi Tanabe Pharma Corporation, Saitama, Japan (T.W., M.K., Ta.S., R.O.); and Safety Research Laboratory, Research Division, Mitsubishi Tanabe Pharma Corporation, Chiba, Japan (M.M., To.S., N.M.).
authors.forename: Naoya
authors.initials: N
authors.lastname: Masutomi
authors.affiliation: DMPK Research Laboratory, Research Division, Mitsubishi Tanabe Pharma Corporation, Saitama, Japan (T.W., M.K., Ta.S., R.O.); and Safety Research Laboratory, Research Division, Mitsubishi Tanabe Pharma Corporation, Chiba, Japan (M.M., To.S., N.M.).
authors.forename: Takesada
authors.initials: T
authors.lastname: Shimura
authors.affiliation: DMPK Research Laboratory, Research Division, Mitsubishi Tanabe Pharma Corporation, Saitama, Japan (T.W., M.K., Ta.S., R.O.); and Safety Research Laboratory, Research Division, Mitsubishi Tanabe Pharma Corporation, Chiba, Japan (M.M., To.S., N.M.).
authors.forename: Rikiya
authors.initials: R
authors.lastname: Ohashi
mesh_terms: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors*; D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D001219:Aspartate Aminotransferases / Q000378:metabolism; D001647:Bile Acids and Salts / Q000097:blood*; D001663:Bilirubin / Q000097:blood*; D002478:Cells, Cultured; D016572:Cyclosporine / Q000493:pharmacokinetics / Q000494:pharmacology; D004347:Drug Interactions; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors*; D029363:Organic Anion Transporters, Sodium-Dependent / Q000037:antagonists & inhibitors*; D017207:Rats, Sprague-Dawley; D012293:Rifampin / Q000493:pharmacokinetics / Q000494:pharmacology; D013379:Substrate Specificity; D027981:Symporters / Q000037:antagonists & inhibitors*
chemical_list: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; C490548:Abcb11 protein, rat; C423013:Abcc2 protein, rat; D001647:Bile Acids and Salts; D027361:Organic Anion Transporters; D029363:Organic Anion Transporters, Sodium-Dependent; D027981:Symporters; C071908:sodium-bile acid cotransporter; D016572:Cyclosporine; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D001663:Bilirubin; D012293:Rifampin