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 < 2 h after dosing with an elimination t½ 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 t½ of 40 h. Levels of the perindopril glucuronide peaked ∼0.5 h later than perindopril, with an elimination t½ of ∼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 pre-dose 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.
- Steady state