title: Interference with bile salt export pump function is a susceptibility factor for human liver injury in drug development.
abstract: The bile salt export pump (BSEP) is an efflux transporter, driving the elimination of endobiotic and xenobiotic substrates from hepatocytes into the bile. More specifically, it is responsible for the elimination of monovalent, conjugated bile salts, with little or no assistance from other apical transporters. Disruption of BSEP activity through genetic disorders is known to manifest in clinical liver injury such as progressive familial intrahepatic cholestasis type 2. Drug-induced disruption of BSEP is hypothesized to play a role in the development of liver injury for several marketed or withdrawn therapeutics. Unfortunately, preclinical animal models have been poor predictors of the liver injury associated with BSEP interference observed for humans, possibly because of interspecies differences in bile acid composition, differences in hepatobiliary transporter modulation or constitutive expression, as well as other mechanisms. Thus, a BSEP-mediated liver liability may go undetected until the later stages of drug development, such as during clinical trials or even postlicensing. In the absence of a relevant preclinical test system for BSEP-mediated liver injury, the toxicological relevance of available in vitro models to human health rely on the use of benchmark compounds with known clinical outcomes, such as marketed or withdrawn drugs. In this study, membrane vesicles harvested from BSEP-transfected insect cells were used to assess the activity of more than 200 benchmark compounds to thoroughly investigate the relationship between interference with BSEP function and liver injury. The data suggest a relatively strong association between the pharmacological interference with BSEP function and human hepatotoxicity. Although the most accurate translation of risk would incorporate pharmacological potency, pharmacokinetics, clearance mechanisms, tissue distribution, physicochemical properties, indication, and other drug attributes, the additional understanding of a compound's potency for BSEP interference should help to limit or avoid BSEP-related liver liabilities in humans that are not often detected by standard preclinical animal models.
authors.affiliation: Department of Comparative Biology and Safety Sciences Amgen Inc., Thousand Oaks, California 91320, USA.
authors.forename: Ryan E
authors.initials: RE
authors.lastname: Morgan
authors.forename: Michael
authors.initials: M
authors.lastname: Trauner
authors.forename: Carlo J
authors.initials: CJ
authors.lastname: van Staden
authors.forename: Paul H
authors.initials: PH
authors.lastname: Lee
authors.forename: Bharath
authors.initials: B
authors.lastname: Ramachandran
authors.forename: Michael
authors.initials: M
authors.lastname: Eschenberg
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Afshari
authors.forename: Charles W
authors.initials: CW
authors.lastname: Qualls
authors.forename: Ruth
authors.initials: R
authors.lastname: Lightfoot-Dunn
authors.forename: Hisham K
authors.initials: HK
authors.lastname: Hamadeh
mesh_terms: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D001681:Biological Assay; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000378:metabolism; D022162:Cytoplasmic Vesicles / Q000187:drug effects / Q000378:metabolism; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D015203:Reproducibility of Results; D018411:Spodoptera / Q000166:cytology; D014162:Transfection; D015262:Xenobiotics / Q000633:toxicity*
chemical_list: C093491:ABCB11 protein, human; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D015262:Xenobiotics