Fujioka Haruto, Hieda Yuhzo, Kuramoto Yasuhiro, Konishi Kanayo, Kinoshita-Kikuta Emiko, Kinoshita Eiji, Koike Tohru
Laboratory of Organic Medicinal Chemistry, Faculty of Pharmacy & Pharmaceutical Sciences, Fukuyama University.
Yakugaku Zasshi. 2013;133(10):1135-41. doi: 10.1248/yakushi.13-00188. Epub 2013 Jul 30.
Enalaprilat (H2L), which is the active metabolite of the pro-drug enalapril, is an angiotensin-converting enzyme inhibitor. Some side effects such as neurodegeneration and taste disorder can be related to copper or zinc deficiency, which would be caused by the metal complex formation of dianionic elalaprilat (L(2-)). For a better understanding of this phenomenon, we investigated the solution species of enalaprilat in the presence of copper(II) or zinc(II) ions by pH titration analysis with I=0.10 M (NaCl) at 25℃. The 1:1 complex formation constants (KML=[ML]/[M(2+)][L(2-)] M(-1)) of 10(7.4) for CuL and 10(4.4) for ZnL complexes were evaluated, indicating the presence of those complexes at a physiological pH. Furthermore, partition experiments with a two-phase system of 1-butanol/water at 25℃ disclosed that copper(II) and zinc(II) complexes of enalaprilat were partially extracted into the organic layer. In the absence of those metal ions, enalaprilat was not soluble in the 1-butanol phase. The increase in lipophilicity of enalaprilat by metal complexation suggests that the long-term administration of enalapril could be a possible risk factor for the disrupted distribution of those metal ions in biological systems.
依那普利拉（H2L）是前体药物依那普利的活性代谢产物，是一种血管紧张素转换酶抑制剂。一些副作用，如神经退行性变和味觉障碍，可能与铜或锌缺乏有关，这是由二价阴离子依那普利拉（L(2-)）形成金属络合物所导致的。为了更好地理解这一现象，我们在25℃、I = 0.10 M（NaCl）条件下，通过pH滴定分析研究了依那普利拉在铜（II）或锌（II）离子存在下的溶液物种。评估得出CuL络合物的1:1络合形成常数（KML = [ML]/[M(2+)][L(2-)] M(-1)）为10(7.4)，ZnL络合物的为10(4.4)，表明在生理pH下存在这些络合物。此外，在25℃下用1-丁醇/水两相系统进行的分配实验表明，依那普利拉的铜（II）和锌（II）络合物部分被萃取到有机层中。在没有这些金属离子的情况下，依那普利拉不溶于1-丁醇相。依那普利拉通过金属络合增加亲脂性表明，长期服用依那普利可能是生物系统中这些金属离子分布紊乱的一个潜在风险因素。
