Quantitative Systems Toxicology Modeling Predicts that Reduced Biliary Efflux Contributes to Tolvaptan Hepatotoxicity.

ABSTRACT: Patients with autosomal dominant polycystic kidney disease (ADPKD) exhibit enhanced susceptibility to tolvaptan hepatotoxicity relative to other patient populations. In a rodent model of ADPKD, the expression and function of the biliary efflux transporter Mrp2 was reduced, and biliary excretion of a major tolvaptan metabolite (DM-4103) was decreased. The current study investigated whether reduced biliary efflux could contribute to increased susceptibility to tolvaptan-associated hepatotoxicity using a quantitative systems toxicology (QST) model (DILIsym). QST simulations revealed that decreased biliary excretion of DM-4103, but not tolvaptan, resulted in substantial hepatic accumulation of bile acids, decreased electron transport chain activity, reduced hepatic adenosine triphosphate conce

SUBMITTER: Beaudoin JJ 

PROVIDER: S-EPMC7854848 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature