Camenisch, Gian P. (2019) DRUG-INDUCED LIVER INJURY PREDICTIONS: EXTENDED CLEARANCE MODEL AND ITS USE FOR PROPSPECTIVE TRANSPORTER- AND ENZYME-BASED HEPATIC CELL STRESS GRADING. International Journal of Pharmacy and Chemistry, 5 (2). pp. 15-19. ISSN 2575-5730

Abstract

Many enzymes and transporters involved in the hepatic clearance of drugs also play an important role in endogenous compound transport. Inhibition of some of these active mechanisms has frequently been shown to be associated with Drug-Induced Liver Injury (DILI). The Extended Clearance Model (ECM) describes the complex interplay between the different processes driving hepatic clearance, namely sinusoidal uptake and efflux, canalicular secretion and intracellular metabolism. Based on the ECM, we have derived an integral concept (referred as 1/R-value approach) to quantitatively describe the overall inhibition potency of potential drug candidates on active processes involved in the transport and metabolism of endogenous and safety-relevant compounds. For a small in-house subset of compounds with complete in vitro data, faultless ECM-based prediction of DILI was realized. Additionally, prediction of several cases of DILI for external compounds was achieved with no major false-positive results (but a large number of false-negatives likely due to incomplete in vitro datasets). Large-scale sharing of data will be needed in order to expand the evaluable dataset and allow more accurate DILI prediction in the future.

Item Type:	Article
Keywords:	DILI, ECM, cell stress, enzyme and transporter inhibition, BDDCS
Date Deposited:	10 Aug 2019 00:45
Last Modified:	10 Aug 2019 00:45
URI:	https://oak.novartis.com/id/eprint/38832