In Vitro Drug-Induced Liver Injury Prediction: Criteria Optimization of Efflux Transporter IC50 and Physicochemical Properties.

Autor:	Yucha RW; Takeda Pharmaceuticals, Drug Metabolism and Pharmakokinetics, Cambridge, Massachusetts, USA., He K; Biotranex, LLC, Monmouth Junction, New Jersey, USA., Shi Q; Biotranex, LLC, Monmouth Junction, New Jersey, USA., Cai L; Biotranex, LLC, Monmouth Junction, New Jersey, USA., Nakashita Y; Takeda Pharmaceutical Company Limited, Drug Safety Research Laboratories, Kanagawa, Japan., Xia CQ; Takeda Pharmaceuticals, Drug Metabolism and Pharmakokinetics, Cambridge, Massachusetts, USA., Liao M; Takeda Pharmaceuticals, Drug Metabolism and Pharmakokinetics, Cambridge, Massachusetts, USA.
Jazyk:	angličtina
Zdroj:	Toxicological sciences : an official journal of the Society of Toxicology [Toxicol Sci] 2017 Jun 01; Vol. 157 (2), pp. 487-499.
DOI:	10.1093/toxsci/kfx060
Abstrakt:	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. (© The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)
Databáze:	MEDLINE
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