PHARMACOKINETICS AND BIOCHEMICAL EFFICACY OF IDRAPRIL CALCIUM, A NOVEL ACE-INHIBITOR, AFTER MULTIPLE ORAL-ADMINISTRATION IN HUMANS

1 The pharmacokinetic profile and biochemical efficacy of idrapril cal cium, a novel angiotensin converting enzyme (ACE) inhibitor, were eval uated in healthy volunteers after multiple dosing for 5 days at the do ses of 100, 200 and 400 mg twice daily. The study was conducted as a d ouble-blind, cross-over comparison of idrapril calcium against placebo . 2 Plasma concentrations of idrapril were determined by an indirect e nzymatic method. Urinary concentrations were measured by reverse phase high performance liquid chromatography (h.p.l.c.). Plasma samples wer e also analysed for ACE activity. 3 The pharmacokinetics of idrapril c alcium did not change significantly between day 1 and day 5. The value s of C-max and AUC were dose-related over the range of doses tested; t (max) was 3-4 h and apparent elimination half-life was 1.4-1.6 h. 4 Pl asma ACE activity was maximally inhibited (94-96%) at all dose levels and remained more than 80% depressed from 2 to at least 6 h after idra pril calcium. Although the maximum effect was not dose-related, the du ration of inhibition showed some dose-dependency, ACE activity returni ng to 56, 45 and 29% of the basal value 12 h after the 100, 200 and 40 0 mg doses, respectively. 5 There were no clinically significant adver se events experienced by the volunteers. No dose-related effects on bl ood pressure or heart rate were observed. There were no changes in cli nical pathology tests, urine analyses or electrocardiograms after dosi ng with idrapril calcium. 6 Idrapril calcium, the prototype of a new c lass of ACE inhibitors, appears to be well-tolerated. Its pharmacokine tics were not significantly changed after repeated administration in m an. Plasma ACE activity was markedly depressed for more than 12 h even after the lowest dose tested (100 mg) and inhibition was correlated t o the levels of circulating drug, the ex vivo IC50 being (12 ng ml(-1) ) on day 1 and day 5.