title: In Vitro Drug-Induced Liver Injury Prediction: Criteria Optimization of Efflux Transporter IC50 and Physicochemical Properties.
abstract: Drug-induced liver injury (DILI) is a severe drug adverse response, which cannot always be reliably predicted in preclinical or clinical studies. Lack of observation of DILI during preclinical and clinical drug development has led to DILI being a leading cause of drug withdrawal from the market. As DILI is potentially fatal, pharmaceutical companies have been developing in vitro tools to screen for potential liver injury. Screens for physicochemical properties, mitochondrial function, and transport protein inhibition have all been employed to varying degrees of success. In vitro inhibition of the bile salt export pump (BSEP) has become a major risk factor for in vivo DILI predictions, yet discrepancies exist in which methods to use and the extent to which BSEP inhibition predicts clinical DILI. The presented work focuses on optimizing DILI predictions by comparing BSEP inhibition via the membrane vesicle assay and the hepatocyte-based BSEPcyte assay, as well as dual and triple liabilities. BSEP transport inhibition of taurcholic acids and glycocholic acids were similar for up to 29 drugs tested, in both the vesicle and hepatocyte-based assays. Positive and negative DILI predictions were optimized at a 50-µM cutoff value for 50 drugs using both NIH Livertox and PharmaPendium databases. Additionally, dual inhibition of BSEP and other efflux transporters (multidrug resistance-associated protein [MRP]2, MRP3, or MRP4) provided no observable predictive benefit compared with BSEP inhibition alone. Eighty-five percent of drugs with high molecular weight (>600 Da), high cLogP (>3), or a daily dose >100 mg and BSEP inhibition were associated with DILI. Triple liability of BSEP inhibition, high molecular weight, and high cLogP attained a 100% positive prediction rate.
authors.affiliation: Takeda Pharmaceuticals, Drug Metabolism and Pharmakokinetics, Cambridge, Massachusetts, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Yucha
authors.affiliation: Biotranex, LLC, Monmouth Junction, New Jersey, USA.
authors.forename: Kan
authors.initials: K
authors.lastname: He
authors.affiliation: Biotranex, LLC, Monmouth Junction, New Jersey, USA.
authors.forename: Qin
authors.initials: Q
authors.lastname: Shi
authors.affiliation: Biotranex, LLC, Monmouth Junction, New Jersey, USA.
authors.forename: Lining
authors.initials: L
authors.lastname: Cai
authors.affiliation: Takeda Pharmaceutical Company Limited, Drug Safety Research Laboratories, Kanagawa, Japan.
authors.forename: Yukie
authors.initials: Y
authors.lastname: Nakashita
authors.affiliation: Takeda Pharmaceuticals, Drug Metabolism and Pharmakokinetics, Cambridge, Massachusetts, USA.
authors.forename: Cindy Q
authors.initials: CQ
authors.lastname: Xia
authors.affiliation: Takeda Pharmaceuticals, Drug Metabolism and Pharmakokinetics, Cambridge, Massachusetts, USA.
authors.forename: Mingxiang
authors.initials: M
authors.lastname: Liao
mesh_terms: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11 / Q000037:antagonists & inhibitors*; D002478:Cells, Cultured; D055598:Chemical Phenomena; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000378:metabolism; D064420:Drug-Related Side Effects and Adverse Reactions / Q000209:etiology* / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D000089762:Multidrug Resistance-Associated Protein 2; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D011237:Predictive Value of Tests; D012307:Risk Factors
chemical_list: C000715087:ABCC2 protein, human; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D000089762:Multidrug Resistance-Associated Protein 2; D004364:Pharmaceutical Preparations
keywords: bile salt export pump (BSEP); drug-induced liver injury (DILI); efflux transport; multidrug resistance protein 3 (MDR3); multidrug resistance-associated protein (MRP); physicochemical properties