PHARMACOKINETICS OF THE ANGIOTENSIN-CONVERTING-ENZYME INHIBITOR, BENAZEPRIL, AND ITS ACTIVE METABOLITE, BENAZEPRILAT, IN DOG

1. The pharmacokinetics of the angiotensin-converting-enzyme (ACE) inh ibitor benazepril were evaluated in eight healthy Beagle dogs. Benazep ril was administered orally at a dosage of 7.5 mg (about 0.5 mg/kg) bo th as a single dose and then once daily for 14 consecutive days. The p rodrug, benazepril, and its active metabolite, benazeprilat, were meas ured in plasma using a gas chromatography mass-spectrometry method wit h mass-selective detection. 2. Benazepril appeared quickly in the plas ma (t(max) 0.5 h) and was rapidly eliminated by metabolism to benazepr ilat. Peak benazeprilat concentrations were attained later (t(max) 1.2 5 h) and declined biphasically with a rapid elimination phase (t(1/2)l ambda(1) 1.1 and 1.7 h after single and the last repeated dose respect ively) followed by a terminal elimination phase (t(1/2)lambda(z) 11.7 and 19.0 h after single and repeated dose respectively). The mean resi dence time for benazeprilat was 15.2 h after the single dose and 17.4 h after the 14th dose. 3. Repeated administration of benazepril produc ed moderate bioaccumulation of benazeprilat; the ratio of AUC([0-->24h ])'s after the 14th dose as compared with the single dose was 1.47, eq uivalent to a half-life for accumulation (t(1/2ace)) of 14.6 h. Steady -state benazeprilat concentrations at peak (C-max) and trough (C-min) were reached within three doses. 4. The pharmacodynamics of benazepril were assessed by measurement of plasma ACE activity. After both singl e doses and at steady-state, benazepril produced inhibition of ACE act ivity in all dogs that was maximal at peak effect (E-max = 100%) and l ong-lasting (> 85% inhibition was present at 24 h). The long duration of action of benazepril on plasma ACE is due to the presence of the te rminal elimination phase of benazeprilat, even though most of the meta bolite is rapidly eliminated from the plasma.