title: [Increase in lipophilicity of enalaprilat by complexation with copper(II) or zinc(II) Ions].
abstract: 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.
authors.affiliation: Laboratory of Organic Medicinal Chemistry, Faculty of Pharmacy & Pharmaceutical Sciences, Fukuyama University.
authors.forename: Haruto
authors.initials: H
authors.lastname: Fujioka
authors.forename: Yuhzo
authors.initials: Y
authors.lastname: Hieda
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kuramoto
authors.forename: Kanayo
authors.initials: K
authors.lastname: Konishi
authors.forename: Emiko
authors.initials: E
authors.lastname: Kinoshita-Kikuta
authors.forename: Eiji
authors.initials: E
authors.lastname: Kinoshita
authors.forename: Tohru
authors.initials: T
authors.lastname: Koike
mesh_terms: D020001:1-Butanol; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000009:adverse effects; D002614:Chelating Agents; D003300:Copper / Q000172:deficiency; D004656:Enalapril; D015773:Enalaprilat / Q000009:adverse effects; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D007477:Ions; D019636:Neurodegenerative Diseases / Q000139:chemically induced; D011355:Prodrugs; D012995:Solubility; D012996:Solutions; D013651:Taste Disorders / Q000139:chemically induced; D014867:Water; D015032:Zinc / Q000172:deficiency
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D002614:Chelating Agents; D007477:Ions; D011355:Prodrugs; D012996:Solutions; D014867:Water; D004656:Enalapril; D003300:Copper; D020001:1-Butanol; D015773:Enalaprilat; D015032:Zinc