A PHARMACODYNAMIC AND PHARMACOKINETIC COMPARISON OF INTRAVENOUS QUINAPRILAT AND ORAL QUINAPRIL

Quinaprilat is the active metabolite of quinapril, an orally active an giotensin-converting enzyme (ACE) inhibitor. The dose-response and dur ation-of-effect after single intravenous doses of quinaprilat and plac ebo (part A) and after administration of oral quinapril solution and i ntravenous quinaprilat (part B) were assessed in a randomized, crossov er study of two groups of 12 healthy volunteers. Pharmacodynamic effec ts of quinaprilat and oral quinapril were assessed by measurement of b lood pressure changes after an infusion of angiotensin I IA-I) at a do se previously determined to produce an increase in diastolic blood pre ssure of 25 mmHg under standardized conditions (A I presser response). A clear dose-response relationship was demonstrated for quinaprilat i n this pharmacodynamic model, with 0.5 mg as the lowest effective dose . Doses of 1.0 mg and higher partially suppressed A-I presser response for at least 6 hours. Onset of action was observed within 15 minutes of intravenous administration of quinaprilat and was independent of do se, whereas peak effect and duration of action appeared to be dose rel ated. Quinaprilat doses of 2.5 mg and 10 mg achieved approximately 50% and >80% inhibition of the A-I presser response, respectively. In par t B, these doses of intravenous quinaprilat were compared with oral do ses of quinapril previously found to produce 50% (2.5 mg) and 90% (10 mg) inhibition of the A-I presser response. The magnitude of effect wa s similar after administration of 20 mg quinapril orally and 10 mg qui naprilat intravenously. Duration of action was longer, however, after administration of intravenous quinaprilat (10 mg) than after oral quin april (20 mg), due to the higher maximum plasma concentration (C-max) of quinaprilat. Mean area under the plasma concentration-time curve ex trapolated to infinity (AUC(0-infinity)) of quinaprilat was similar af ter the 10-mg dose ef intravenous quinaprilat and the 20-mg dose of or al quinapril. Based on the concentrations of quinaprilat observed in t his study, the absolute bioavailability of quinapril was approximately 50%; intravenous quinaprilat should therefore produce a pharmacodynam ic response similar to that obtained with oral quinapril at approximat ely half the dose.