title: Antibiotic-Induced Elevations of Plasma Bile Acids in Rats Independent of Bsep Inhibition.
abstract: Drug-induced liver injury (DILI) is a common toxicity observed in drug development and can lead to withdrawal of approved drugs from the market. To better understand the numerous mechanisms of DILI, recent efforts have focused on transporter inhibition, specifically liver canalicular bile salt export pump (Bsep) as one mechanism of DILI, and on the potential use of plasma bile acids as monitorable mechanism-based biomarkers of Bsep inhibition. To explore alternative mechanisms of bile acid increases in plasma, 6 antibiotic and 2 nonantibiotic drugs unlikely to be Bsep inhibitors were evaluated in rat studies. Surprisingly, all 6 antibiotics demonstrated 2- to 14-fold increases of plasma taurocholic acid (TCA). Also, unconjugated primary bile acids and secondary bile acids (both taurine-conjugated and unconjugated) were decreased in rat plasma after antibiotic treatments, but not with the nonantibiotic drugs. These results suggest alternative mechanisms of bile acids regulation such as attenuation of bacterial deconjugation of bile acids following reduction of gut microflora by antibiotics. Measurements of TCA transport in rat hepatocytes and Bsep-containing membrane vesicles suggest that inhibition of uptake into hepatocytes could also contribute to increases in plasma bile acid concentrations, while excluding inhibition of Bsep as a mechanism. These studies further demonstrate that there are several mechanisms that can lead to conjugated bile acid increases in plasma. By carefully considering the time course and magnitude of changes of individual bile acids relative to any changes seen in transaminases and bilirubin, interpretations and conclusions of the involvement of Bsep inhibition are enabled.
authors.affiliation: Safety Assessment and Laboratory Animal Resources, West Point, Pennsylvania, USA.
authors.forename: Yutai
authors.initials: Y
authors.lastname: Li
authors.affiliation: Pharmacokinetics Pharmacodynamics and Drug Metabolism, Rahway, New Jersey, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hafey
authors.affiliation: Safety Assessment and Laboratory Animal Resources, West Point, Pennsylvania, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Duong
authors.affiliation: Pharmacokinetics Pharmacodynamics and Drug Metabolism, Kenilworth, New Jersey, USA.
authors.forename: Raymond
authors.initials: R
authors.lastname: Evers
authors.affiliation: Biometrics Research, MRL, West Point, Pennsylvania, USA.
authors.forename: Kyeongmi
authors.initials: K
authors.lastname: Cheon
authors.affiliation: Biometrics Research, MRL, West Point, Pennsylvania, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Holder
authors.affiliation: Safety Assessment and Laboratory Animal Resources, West Point, Pennsylvania, USA.
authors.forename: Alema
authors.initials: A
authors.lastname: Galijatovic-Idrizbegovic
authors.affiliation: Safety Assessment and Laboratory Animal Resources, West Point, Pennsylvania, USA.
authors.forename: Frank D
authors.initials: FD
authors.lastname: Sistare
authors.affiliation: Safety Assessment and Laboratory Animal Resources, West Point, Pennsylvania, USA.
authors.forename: Warren E
authors.initials: WE
authors.lastname: Glaab
mesh_terms: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11 / Q000037:antagonists & inhibitors*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity*; D001647:Bile Acids and Salts / Q000097:blood*; D002853:Chromatography, Liquid; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D053719:Tandem Mass Spectrometry
chemical_list: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; C490548:Abcb11 protein, rat; D000900:Anti-Bacterial Agents; D001647:Bile Acids and Salts
keywords:  transporters; bile acids; bile salt export pump (BSEP); biomarkers; liquid chromatography-mass spectrometry (lc-ms); microbiome; antibiotics