Physicochemical and enzyme binding kinetic properties of a new angiotensin-converting enzyme inhibitor ramipril and their clinical implications.

After oral administration, ramipril, a nonsulfhydryl angiotensin-converting enzyme (ACE) inhibitor, is transformed in the liver into its active metabolite ramiprilat. Because of its pentane ring it is at least 23 times more lipophilic than enalaprilat. The in vitro affinity for ACE is 7 times higher than for enalaprilat and 47 times higher than for captopril. The ramiprilat-ACE complex is therefore very stable and dissociates 6 times more slowly than the enalaprilat ACE complex and 72 times more slowly than the captopril ACE complex. Consequently, ramipril is pharmacologically more potent and has a longer duration of action than enalapril and captopril. The blood pressure lowering effect of ACE inhibitors is attributed to the decrease in angiotensin II in serum and locally in target organs of hypertension: heart, vessel wall, kidney and brain. Inhibition of tissue renin-angiotensin system by ramipril has been described in target organs of hypertension in animal models and in clinical studies. Possibly due to its high lipophilicity, and strong affinity to the converting enzyme a better tissue penetration and a more pronounced local ACE inhibition in the target organs has been observed, as compared to other ACE inhibitors. In a preliminary investigation a direct action of ramipril on the tissue RAS in hypertensive patients could also be demonstrated.(ABSTRACT TRUNCATED AT 250 WORDS)