orlistat and abiraterone

Abiraterone acetate for metastatic castration-resistant prostate cancer is an acetylated prodrug to be hydrolyzed to abiraterone. Abiraterone acetate is known to be hydrolyzed by pancreatic cholesterol esterase secreted into the intestinal lumen. This study aimed to investigate the possibility that arylacetamide deacetylase (AADAC) expressed in enterocytes contributes to the hydrolysis of abiraterone acetate based on its substrate preference.. Abiraterone acetate hydrolase activity was measured using human intestinal (HIM) and liver microsomes (HLM) as well as recombinant AADAC. Correlation analysis between activity and AADAC expression was performed in 14 individual HIMs. The in vivo pharmacokinetics of abiraterone acetate was examined using wild-type and Aadac knockout mice administered abiraterone acetate with or without orlistat, a pancreatic cholesterol esterase inhibitor.. Recombinant AADAC showed abiraterone acetate hydrolase activity with similar K. AADAC is responsible for the hydrolysis of abiraterone acetate in the intestine and liver, suggesting that concomitant use of abiraterone acetate and drugs potently inhibiting AADAC should be avoided.

Topics: Abiraterone Acetate; Adolescent; Adult; Aged; Androstenes; Animals; Carboxylesterase; Carboxylic Ester Hydrolases; Female; Humans; Hydrolysis; Inhibitory Concentration 50; Intestines; Kinetics; Male; Mice, Knockout; Microsomes, Liver; Middle Aged; Orlistat; Recombinant Proteins