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

Yoshiyuki Sakai, Tatsuki Fukami, Mai Nagaoka, Keiya Hirosawa, Hiroyuki Ichida, Rei Sato, Kohei Suzuki, Masataka Nakano, Miki Nakajima

Life sciences 2021 Nov 01

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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 Km value to HIM and HLM. The positive correlation between activity and AADAC levels in individual HIMs supported the responsibility of AADAC for abiraterone acetate hydrolysis. The area under the plasma concentration-time curve (AUC) of abiraterone after oral administration of abiraterone acetate in Aadac knockout mice was 38% lower than that in wild-type mice. The involvement of pancreatic cholesterol esterase in abiraterone formation was revealed by the decreased AUC of abiraterone by coadministration of orlistat. Orlistat potently inhibited AADAC, implying its potential as a perpetrator of drug-drug interactions. 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. Copyright © 2021 Elsevier Inc. All rights reserved.

Citation

Yoshiyuki Sakai, Tatsuki Fukami, Mai Nagaoka, Keiya Hirosawa, Hiroyuki Ichida, Rei Sato, Kohei Suzuki, Masataka Nakano, Miki Nakajima. Arylacetamide deacetylase as a determinant of the hydrolysis and activation of abiraterone acetate in mice and humans. Life sciences. 2021 Nov 01;284:119896