Yanjiao Xu, Chengliang Zhang, Xiping Li, Tao Wu, Xiuhua Ren, Dong Liu
Department of Pharmacy, Tongji Hospital, Tongji Medical School, Huazhong University of Science and Technology.
Drug Metab Pharmacokinet. 2013;28(6):468-74. doi: 10.2133/dmpk.dmpk-12-rg-143. Epub 2013 May 7.
Human carboxylesterase (CES) 1A and CES2, two major forms of human CES, dominate the pharmacokinetics of most prodrugs such as imidapril and irinotecan (CPT-11). Antihypertensive drugs are often prescribed for clinical therapy concurrently with others. Moreover, two or more antihypertensive drugs are ubiquitously combined. The influences of antihypertensive drugs on the activity of CES remain undefined. In the present study, the inhibitory effects of 17 antihypertensive drugs on the CES1A1 and CES2 activities were evaluated. Imidapril and CPT-11 were used as substrates and cultured with liver microsomes in vitro. The imidapril hydrolase activities by recombinant CES1A1 and human liver microsomes (HLM) were intensely inhibited by telmisartan and nitrendipine (K(i) = 0.49 ± 0.09 and 1.12 ± 0.39 µM for CES1A1, 1.69 ± 0.17 µM and 1.24 ± 0.27 µM for HLM, respectively). However, other drugs did not exert strong inhibition. The enzyme hydrolase activity of recombinant CES2 was substantially inhibited by diltiazem and verapamil (K(i) = 0.25 ± 0.02 and 3.84 ± 0.99 µM, respectively). Hence, diltiazem, verapamil, nitrendipine and telmisartan may attenuate the drug efficacy of catalyzed prodrugs by changing the activities of CES1A1 and CES2.
人羧酸酯酶（CES）1A和CES2是人类CES的两种主要形式，主导着大多数前体药物（如咪达普利和伊立替康（CPT-11））的药代动力学。抗高血压药物在临床治疗中常与其他药物联合使用。此外，两种或更多种抗高血压药物联合使用的情况很普遍。抗高血压药物对CES活性的影响尚不清楚。在本研究中，评估了17种抗高血压药物对CES1A1和CES2活性的抑制作用。以咪达普利和CPT-11为底物，与肝微粒体进行体外培养。替米沙坦和尼群地平强烈抑制重组CES1A1和人肝微粒体（HLM）的咪达普利水解酶活性（CES1A1的K(i)分别为0.49±0.09和1.12±0.39µM，HLM的K(i)分别为1.69±0.17µM和1.24±0.27µM）。然而，其他药物没有产生强烈抑制作用。重组CES2的酶水解活性受到地尔硫卓和维拉帕米的显著抑制（K(i)分别为0.25±0.02和3.84±0.99µM）。因此，地尔硫卓、维拉帕米、尼群地平和替米沙坦可能通过改变CES1A1和CES2的活性来减弱催化前体药物的药效。
