Inhibition of tissue angiotensin converting enzyme by perindopril: in vivo assessment in the rat using radioinhibitor binding displacement.

Changes in angiotensin converting enzyme (ACE) derived from plasma, lung, aorta, brain, kidney and testis were measured in rats treated with perindopril. Angiotensin converting enzyme was measured by a radio inhibitor binding method using 125I351A. Rats were gavage fed perindopril (1, 4 and 8 mg/kg) and changes followed over 48 hr. Plasma and kidney ACE were both affected acutely with reduction of 125I351A binding to less than 5% of that in control animals 1 and 2 hr after gavage. Ligand binding to ACE in plasma and kidney returned to control levels after 24 hr. Ligand binding to ACE in lung, aorta and brain also was displaced after perindopril treatment. Changes were of a lesser degree than in plasma or kidney. Maximal effect was 1 to 4 hr after treatment and persisted through 24 hr postgavage. Ligand binding to ACE from testis was little altered over the time period of study. In a dose varying study rats were gavage fed perindopril (0-32 mg/kg) and tissues were studied 4 hr later. Ligand binding to plasma and kidney ACE was displaced by 50% at a dose of 1 mg/kg or less, whereas a dose of 16 to 32 mg/kg was required for a similar effect on ACE in lung, aorta and brain. ACE in testis was only affected to a small degree at a dose of 32 mg/kg. ACE is tissues was inhibited differentially after oral treatment with perindopril. Although differing in bioavailability, bioactivation of the drug or different binding properties of the enzyme could all account for the results, the most likely explanation is that there is variation in tissue penetration of the drug.