State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, China.
Department of DMPK, Sanofi Company, MA, USA.
Eur J Pharm Sci. 2019 Mar 15;130:156-165. doi: 10.1016/j.ejps.2019.01.010. Epub 2019 Jan 26.
1-aminobenzotriazole (ABT) is a known P450 enzyme non-selective inactivator that serves as a tool for assessing P450-mediated metabolism. However, many findings demonstrated that ABT was ineffective with human CYP2C9. A profound pan-CYP450 inhibitor is desired avoid the risk of incomplete inhibition of P450, especially CYP2C9. Atipamezole is commonly used to recover animals from sedation-anesthesia induced by αadrenoceptor agonists. The purpose of this study is to evaluate atipamezole as a non-selective inhibitor of P450 enzymes and compare it with ABT. Inhibition toward seven major human CYP450 isoform was determined for atipamezole and ABT in human, rat, and dog liver microsomes for the direct and time-dependent inhibition potentials. IC values toward human and animal CYPs without preincubation are 0.02-7.93 μM and 20.9-1798 μM for atipamezole and ABT, respectively. The IC values of ABT after preincubation shift to 4.06-460 μM. Atipamezole has more effective inhibition to CYP2C9 mediated diclofenac hydroxylation in human and animal liver microsomes with IC values of 1.50-5.20 μM than that of ABT at 74.7-460 μM. No IC shift was observed for atipamezole to CYP isoforms. In vivo utility of atipamezole was assessed by co-dosing with diclofenac in rats. At 30 mg/kg via oral, atipamezole enhanced the AUC of diclofenac by 13.1-fold and the C by 5.6-fold. Similar enhancement also achieved for ABT (100 mg/kg) with AUC and C increased 9.5 and 4.8-fold. As a reversible pan-CYP inhibitor, atipamezole showed less species difference than ABT. It provides a better and easier to use alternative to ABT for ADME optimization and elucidating mechanistic drug metabolism or toxicity studies.
1-氨基苯并三唑（ABT）是一种已知的非选择性 P450 酶抑制剂，可用作评估 P450 介导的代谢的工具。然而，许多研究结果表明，ABT 对人 CYP2C9 无效。需要一种强效的泛 CYP450 抑制剂来避免 P450 不完全抑制的风险，特别是 CYP2C9。阿替美唑常用于从α肾上腺素受体激动剂诱导的镇静-麻醉中恢复动物。本研究旨在评估阿替美唑作为 P450 酶的非选择性抑制剂，并将其与 ABT 进行比较。在人、大鼠和狗肝微粒体中，测定了阿替美唑和 ABT 对七种主要人 CYP450 同工型的直接和时间依赖性抑制潜力。无预孵育时，人 CYP 和动物 CYP 的 IC 值分别为 0.02-7.93 μM 和 20.9-1798 μM。预孵育后 ABT 的 IC 值移至 4.06-460 μM。阿替美唑对人肝微粒体和动物肝微粒体中 CYP2C9 介导的双氯芬酸羟化的抑制作用更为有效，其 IC 值分别为 1.50-5.20 μM，而 ABT 的 IC 值为 74.7-460 μM。阿替美唑对 CYP 同工型无 IC 移。通过在大鼠中与双氯芬酸共同给药评估了阿替美唑的体内实用性。口服 30mg/kg 时，阿替美唑使双氯芬酸的 AUC 增加 13.1 倍，C 增加 5.6 倍。ABT（100mg/kg）也达到了类似的增强效果，AUC 和 C 分别增加了 9.5 倍和 4.8 倍。作为一种可逆的泛 CYP 抑制剂，阿替美唑比 ABT 的种间差异更小。它为 ADME 优化以及阐明药物代谢或毒性研究的机制提供了一种更好、更易用的 ABT 替代物。
