Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Japan (K.H., T.F., K.T., Y.S., F.K., Ma.N., Mi.N.); and WPI Nano Life Science Institute, Kakuma-machi, Kanazawa, Japan (T.F., Ma.N., Mi.N.).
Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Japan (K.H., T.F., K.T., Y.S., F.K., Ma.N., Mi.N.); and WPI Nano Life Science Institute, Kakuma-machi, Kanazawa, Japan (T.F., Ma.N., Mi.N.)
Drug Metab Dispos. 2021 Apr;49(4):322-329. doi: 10.1124/dmd.120.000295. Epub 2021 Jan 14.
Human arylacetamide deacetylase (AADAC) plays a role in the detoxification or activation of drugs and is sometimes involved in the incidence of toxicity by catalyzing hydrolysis reactions. AADAC prefers compounds with relatively small acyl groups, such as acetyl groups. Eslicarbazepine acetate, an antiepileptic drug, is a prodrug rapidly hydrolyzed to eslicarbazepine. We sought to clarify whether AADAC might be responsible for the hydrolysis of eslicarbazepine acetate. Eslicarbazepine acetate was efficiently hydrolyzed by human intestinal and liver microsomes and recombinant human AADAC. The hydrolase activities in human intestinal and liver microsomes were inhibited by epigallocatechin gallate, a specific inhibitor of AADAC, by 82% and 88% of the control, respectively. The hydrolase activities in liver microsomes from 25 human livers were significantly correlated ( = 0.87, < 0.001) with AADAC protein levels, suggesting that the enzyme AADAC is responsible for the hydrolysis of eslicarbazepine acetate. The effects of genetic polymorphisms of on eslicarbazepine acetate hydrolysis were examined by using the constructed recombinant AADAC variants with T74A, V172I, R248S, V281I, N366K, or X400Q. AADAC variants with R248S or X400Q showed lower activity than wild type (5% or 21%, respectively), whereas those with V172I showed higher activity than wild type (174%). Similar tendencies were observed in the other four substrates of AADAC; that is, -nitrophenyl acetate, ketoconazole, phenacetin, and rifampicin. Collectively, we found that eslicarbazepine acetate is specifically and efficiently hydrolyzed by human AADAC, and several polymorphic alleles would be a factor affecting the enzyme activity and drug response. SIGNIFICANCE STATEMENT: This is the first study to clarify that arylacetamide deacetylase (AADAC) is responsible for the activation of eslicarbazepine acetate, an antiepileptic prodrug, to eslicarbazepine, an active form, in the human liver and intestines. In addition, we found that several polymorphic alleles would be a factor affecting the enzyme activity and drug response.
人类芳基乙酰胺脱乙酰酶 (AADAC) 在药物的解毒或激活中发挥作用，有时通过催化水解反应参与毒性的发生。AADAC 更喜欢相对较小的酰基化合物，如乙酰基。艾司利卡巴西片是一种抗癫痫药物，是一种前药，可迅速水解为艾司利卡巴西。我们试图阐明 AADAC 是否可能负责艾司利卡巴西片的水解。艾司利卡巴西片被人肠和肝微粒体以及重组人 AADAC 有效水解。芳基乙酰胺脱乙酰酶的特异性抑制剂表没食子儿茶素没食子酸酯分别抑制人肠和肝微粒体中的水解酶活性 82%和 88%。25 个人肝微粒体中的水解酶活性与 AADAC 蛋白水平显著相关（=0.87，<0.001），表明酶 AADAC 负责艾司利卡巴西片的水解。通过使用构建的具有 T74A、V172I、R248S、V281I、N366K 或 X400Q 的重组 AADAC 变体，研究了对艾司利卡巴西片水解的遗传多态性的影响。与野生型相比，具有 R248S 或 X400Q 的 AADAC 变体的活性较低（分别为 5%或 21%），而具有 V172I 的变体的活性较高（174%）。在 AADAC 的其他四个底物中也观察到类似的趋势，即-硝基苯乙酸酯、酮康唑、非那西汀和利福平。总的来说，我们发现艾司利卡巴西片被人 AADAC 特异性且有效地水解，几个 多态性等位基因将是影响酶活性和药物反应的一个因素。
这是第一项研究，阐明芳基乙酰胺脱乙酰酶（AADAC）负责艾司利卡巴西片（一种抗癫痫前药）在人肝和肠道中转化为艾司利卡巴西（一种活性形式）。此外，我们发现几个 多态性等位基因将是影响酶活性和药物反应的一个因素。
