title: The lipophilic properties of angiotensin I-converting enzyme inhibitors do not influence their diffusion through cultured endothelium.
abstract: The background for these investigations was the discovery that formation of angiotensin II by the renin angiotensin system can take place in extravascular tissues (e.g., cardiomyocytes and neurons) and within single cells. Consequently, the question arose about whether such tissue-based systems might be differentially influenced by angiotensin I-converting enzyme (ACE) inhibitors with distinct physicochemical properties. Therefore, the aim of this study was to investigate how the membrane penetration of various ACE inhibitors depends on their lipophilia. All diacid forms of ACE inhibitors are dissociated at a pH of 7.4 and scarcely extractable into octanol (extraction coefficient < 10%). In contrast, the extraction coefficients of the parent substances showed marked differences in the following order of increasing lipophilia: enalapril = perindopril < captopril = ceranapril < ramipril < quinapril < HOE288 = zofenopril < fosinopril < HOE065. For selected substances, the kinetics of diffusion through a monolayer of cultured bovine aortic endothelium were determined. The diffusion rates (expressed as half lives) of captopril (59.6 min), enalapril (53.4 min), enalaprilat (50.8 min), ramipril (56.9 min) and ramiprilat (51.1 min) are similar indicating: 1) that penetration is independent on lipophilia and 2) that endothelium constitutes no specific barrier for the passage of ACE inhibitors into the vessel wall.
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, Medical University of Lübeck, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Raasch
authors.forename: A
authors.initials: A
authors.lastname: Dendorfer
authors.forename: B
authors.initials: B
authors.lastname: Ball
authors.forename: P
authors.initials: P
authors.lastname: Dominiak
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology / Q000187:drug effects; D002417:Cattle; D002478:Cells, Cultured; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004058:Diffusion; D004730:Endothelium, Vascular / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D007202:Indicators and Reagents; D008055:Lipids / Q000737:chemistry; D011355:Prodrugs
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D007202:Indicators and Reagents; D008055:Lipids; D011355:Prodrugs