Single-dose and steady-state pharmacokinetics and pharmacodynamics of perindopril in hypertensive subjects

• Published in: Journal of cardiovascular pharmacology Vol. 20; no. 3; p. 505
• Main Authors: Louis, W J, Workman, B S, Conway, E L, Worland, P, Rowley, K, Drummer, O, McNeil, J J, Harris, G, Jarrott, B
• Format: Journal Article
• Language: English
• Published: United States 01.09.1992
• Subjects: Aged; Angiotensin-Converting Enzyme Inhibitors - pharmacokinetics; Angiotensin-Converting Enzyme Inhibitors - pharmacology; Blood Pressure - drug effects; Chromatography, Ion Exchange; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Hypertension - blood; Hypertension - drug therapy; Hypertension - physiopathology; Indoles - pharmacokinetics; Indoles - pharmacology; Male; Middle Aged; Peptidyl-Dipeptidase A - blood; Perindopril; Radioimmunoassay
• ISSN: 0160-2446
• DOI: 10.1097/00005344-199209000-00024

In a double-blind, placebo-controlled, parallel group study, 24 essential hypertensive subjects were randomised to receive either placebo or 2, 4, or 8 mg perindopril. Perindopril, its deesterified metabolite, perindoprilat, and perindoprilat glucuronide were separated with an ion-exchange resin and determined by a radioimmunoassay (RIA). Pharmacokinetic and pharmacodynamic parameters were estimated for 96 h after the first dose and after 4-week once-daily treatment. Perindopril peak levels were achieved in less than or equal to 2 h after dosing with an elimination t1/2 of 1-2 h. Peak levels of perindoprilat were achieved more slowly, reaching a maximum level 5-8 h after dosing, and had an elimination t1/2 of 40 h. Levels of the perindopril glucuronide peaked approximately 0.5 h later than perindopril, with an elimination t1/2 of approximately 2 h. Perindopril, perindoprilat, and its glucuronide conjugate followed linear kinetics in the dose range of 2-8 mg, and there was no evidence of accumulation with chronic dosing. Perindopril 4 and 8 mg produced significant decreases in predose blood pressure (BP) with chronic dosing, with maximal decreases occurring 5-7 h after dosing. Perindopril also produced a prolonged dose-dependent inhibition of plasma angiotensin-converting enzyme (ACE) activity that was maximum after 4 h and had not fully recovered by 48 h after a single dose.