Mitigating the Inhibition of Human Bile Salt Export Pump by Drugs: Opportunities Provided by Physicochemical Property Modulation, In Silico Modeling, and Structural Modification

• DOI: 10.1124/dmd.112.047068
• Publication Date: 2012-09-08T05:41:21Z
• Authors: Daniel J. Warner; Hongming Chen; Louis-David Cantin; J. Gerry Kenna; Simone Stahl; Clare L. Walker; Tobias Noeske
• Keywords: Bile Acids and Salts; 0301 basic medicine; 03 medical and health sciences; Animals; Humans; Quantitative Structure-Activity Relationship; ATP-Binding Cassette Transporters; Chemical and Drug Induced Liver Injury; ATP Binding Cassette Transporter, Subfamily B, Member 11; Cell Line

The human bile salt export pump (BSEP) is a membrane protein expressed on the canalicular plasma domain of hepatocytes, which mediates active transport unconjugated and conjugated salts from liver cells into bile. BSEP activity therefore plays an important role in flow. In humans, genetically inherited defects expression or cause cholestatic injury, many drugs that drug-induced injury (DILI) humans have been shown to inhibit vitro vivo. These findings suggest inhibition by could be one mechanisms initiate DILI. To gain insight chemical features responsible for inhibition, we used recently described vesicle assay quantify transporter set 624 compounds. relationship between molecular physicochemical properties was investigated, our results show lipophilicity size are significantly correlated with inhibition. This data further build predictive classification models through multiple quantitative structure-activity modeling approaches. highest level accuracy provided support vector machine model (accuracy = 0.87, κ 0.74). analyses highlight potential value can gained combining computational methods experimental efforts early stages drug discovery projects minimize propensity candidates BSEP.