From hazard to risk prioritization: a case study to predict drug-induced cholestasis using physiologically based kinetic modeling.

ABSTRACT: Cholestasis is characterized by hepatic accumulation of bile acids. Clinical manifestation of cholestasis only occurs in a small proportion of exposed individuals. The present study aims to develop a new approach methodology (NAM) to predict drug-induced cholestasis as a result of drug-induced hepatic bile acid efflux inhibition and the resulting bile acid accumulation. To this end, hepatic concentrations of a panel of drugs were predicted by a generic physiologically based kinetic (PBK) drug model. Their effects on hepatic bile acid efflux were incorporated in a PBK model for bile acids. The predicted bile acid accumulation was used as a measure for a drug's cholestatic potency. The selected drugs were known to inhibit hepatic bile acid efflux in an assay with primary suspension-cultured

SUBMITTER: de Bruijn VMP 

PROVIDER: S-EPMC11324677 | biostudies-literature | 2024 Sep

REPOSITORIES: biostudies-literature