Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan; WPI Nano Life Science Institute, Kakuma-machi, Kanazawa 920-1192, Japan.
Life Sci. 2021 Nov 1;284:119896. doi: 10.1016/j.lfs.2021.119896. Epub 2021 Aug 25.
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 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.
醋酸阿比特龙用于转移性去势抵抗性前列腺癌是一种乙酰化前药，在体内被水解为阿比特龙。已知醋酸阿比特龙在肠道腔中分泌的胰腺胆固醇酯酶的作用下水解。本研究旨在基于其底物偏好，研究肠细胞中表达的芳基乙酰胺脱乙酰酶（AADAC）是否有助于醋酸阿比特龙的水解。
使用人肠（HIM）和肝微粒体（HLM）以及重组 AADAC 测量醋酸阿比特龙水解酶活性。在 14 个人 HIM 中进行活性与 AADAC 表达的相关性分析。使用野生型和 Aadac 敲除小鼠，给予醋酸阿比特龙，同时或不给予胰腺胆固醇酯酶抑制剂奥利司他，研究醋酸阿比特龙在体内的药代动力学。
重组 AADAC 显示出与 HIM 和 HLM 相似的 K 值的醋酸阿比特龙水解酶活性。个体 HIM 中活性与 AADAC 水平之间的正相关支持了 AADAC 对醋酸阿比特龙水解的责任。Aadac 敲除小鼠口服醋酸阿比特龙后，阿比特龙的血药浓度-时间曲线下面积（AUC）比野生型小鼠低 38%。奥利司他的共同给药揭示了胰腺胆固醇酯酶在阿比特龙形成中的作用，导致阿比特龙的 AUC 降低。奥利司他强烈抑制 AADAC，暗示其可能成为药物相互作用的罪魁祸首。
AADAC 负责肠道和肝脏中醋酸阿比特龙的水解，表明应避免同时使用醋酸阿比特龙和强烈抑制 AADAC 的药物。
