title: Drug-induced perturbations of the bile acid pool, cholestasis, and hepatotoxicity: mechanistic considerations beyond the direct inhibition of the bile salt export pump.
abstract: The bile salt export pump (BSEP) is located on the canalicular plasma membrane of hepatocytes and plays an important role in the biliary clearance of bile acids (BAs). Therefore, any drug or new chemical entity that inhibits BSEP has the potential to cause cholestasis and possibly liver injury. In reality, however, one must consider the complexity of the BA pool, BA enterohepatic recirculation (EHR), extrahepatic (renal) BA clearance, and the interplay of multiple participant transporters and enzymes (e.g., sulfotransferase 2A1, multidrug resistance-associated protein 2, 3, and 4). Moreover, BAs undergo extensive enzyme-catalyzed amidation and are subjected to metabolism by enterobacteria during EHR. Expression of the various enzymes and transporters described above is governed by nuclear hormone receptors (NHRs) that mount an adaptive response when intracellular levels of BAs are increased. The intracellular trafficking of transporters, and their ability to mediate the vectorial transport of BAs, is governed by specific kinases also. Finally, bile flow, micelle formation, canalicular membrane integrity, and BA clearance can be influenced by the inhibition of multidrug resistant protein 3- or ATPase-aminophospholipid transporter-mediated phospholipid flux. Consequently, when screening compounds in a discovery setting or conducting mechanistic studies to address clinical findings, one has to consider the direct (inhibitory) effect of the parent drug and metabolites on multiple BA transporters, as well as inhibition of BA sulfation and amidation and NHR function. Vectorial BA transport, in addition to BA EHR and homoeostasis, could also be impacted by drug-dependent modulation of kinases and enterobacteria.
authors.affiliation: Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, New Jersey (A.D.R., Y.L.); Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Wallingford, Connecticut (M.S.); Leads Discovery and Optimization, Bristol-Myers Squibb, Princeton, New Jersey (M.E.C.); and Leads Discovery and Optimization, Bristol-Myers Squibb, Wallingford, Connecticut (L.E., T.Z.).
authors.forename: A David
authors.initials: AD
authors.lastname: Rodrigues
authors.forename: Yurong
authors.initials: Y
authors.lastname: Lai
authors.forename: Mary Ellen
authors.initials: ME
authors.lastname: Cvijic
authors.forename: Lisa L
authors.initials: LL
authors.lastname: Elkin
authors.forename: Tatyana
authors.initials: T
authors.lastname: Zvyaga
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Soars
mesh_terms: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001647:Bile Acids and Salts / Q000097:blood / Q000378:metabolism* / Q000652:urine; D001648:Bile Canaliculi / Q000378:metabolism; D001692:Biological Transport; D056486:Chemical and Drug Induced Liver Injury / Q000150:complications / Q000378:metabolism*; D002779:Cholestasis / Q000150:complications / Q000378:metabolism*; D005243:Feces / Q000737:chemistry; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008954:Models, Biological
chemical_list: C093491:ABCB11 protein, human; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D001647:Bile Acids and Salts