Interaction Between Sex and Organic Anion-Transporting Polypeptide 1b2 on the Pharmacokinetics of Regorafenib and Its Metabolites Regorafenib-N-Oxide and Regorafenib-Glucuronide in Mice.

ABSTRACT: Regorafenib, a multikinase inhibitor used in the treatment of various solid tumors, undergoes extensive uridine 5'-diphosphate glucuronosyltransferase (Ugt)1a9-mediated glucuronidation to form regorafenib-N-β-glucuronide (M7; RG), but the contribution of hepatic uptake transporters, such as organic anion-transporting polypeptide (Oatp)1b2, to the pharmacokinetics of regorafenib remains poorly understood. Using NONMEM-based, population-based, parent-metabolite modeling, we found that Oatp1b2 and sex strongly impact the systemic exposure to RG in mice receiving oral regorafenib. Metabolic studies revealed that the liver microsomal expression of cytochrome P450 (Cyp)3a11 is twofold lower in female mice, whereas Ugt1a9 levels and function are not sex dependent. This finding is consistent with

SUBMITTER: Fu Q 

PROVIDER: S-EPMC6662550 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature