Arylacetamide deacetylase as a determinant of the hydrolysis and activation of abiraterone acetate in mice and humans

Abiraterone acetate for metastatic castration-resistant prostate cancer is an acetylated prodrug to be hydrolyzed abiraterone. known by pancreatic cholesterol esterase secreted into the intestinal lumen. This study aimed investigate possibility that arylacetamide deacetylase (AADAC) expressed in enterocytes contributes hydrolysis of abiraterone based on its substrate preference. hydrolase activity was measured using human (HIM) and liver microsomes (HLM) as well recombinant AADAC. Correlation analysis between AADAC expression performed 14 individual HIMs. The vivo pharmacokinetics examined wild-type Aadac knockout mice administered with or without orlistat, a inhibitor. Recombinant showed similar Km value HIM HLM. positive correlation levels HIMs supported responsibility hydrolysis. area under plasma concentration-time curve (AUC) after oral administration 38% lower than mice. involvement formation revealed decreased AUC coadministration orlistat. Orlistat potently inhibited AADAC, implying potential perpetrator drug-drug interactions. responsible intestine liver, suggesting concomitant use drugs inhibiting should avoided.