Walter Raasch, Andreas Dendorfer, Benedikt Ball and Peter Dominiak
Institute of Experimental and Clinical Pharmacology and Toxicology, Medical
University of L�ｪubeck,
Ratzeburger Allee 160, 23538 L�ｪubeck, Germany
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.
Keywords: Lipophilic property, Angiotensin I-converting enzyme (ACE),
ACE inhibitor,
Membrane penetration, Endothelium