Benazepril hydrochloride is a prodrug hydrolysed in vivo to its active metabolite, benazeprilat. Benazeprilat is a highly potent and selective inhibitor of ACE, thus preventing the conversion of inactive angiotensin I to active angiotensin II and thereby also reducing synthesis of aldosterone. Therefore, it blocks effects mediated by angiotensin II and aldosterone, including vasoconstriction of both arteries and veins, retention of sodium and water by the kidney and remodelling effects (including pathological cardiac hypertrophy and degenerative renal changes). Benazeprilat causes long-lasting inhibition of plasma ACE activity in dogs and cats, with more than 95% inhibition at peak effect and significant activity (>80% in dogs and >90% in cats) persisting 24 hours after dosing. Benazepril reduces the blood pressure and volume load on the heart in dogs with congestive heart failure. In cats with experimental renal insufficiency, benazepril normalized the elevated glomerular capillary pressure and reduced the systemic blood pressure. Reduction in glomerular hypertension may retard the progression of kidney disease by inhibition of further damage to the kidneys. Placebo controlled clinical field studies in cats with chronic kidney disease (CKD) have demonstrated that benazepril significantly reduced levels of urine protein and urine protein to creatinine ratio (UPC); this effect is probably mediated via reduced glomerular hypertension and beneficial effects on the glomerular basement membrane. No effect of benazepril hydrochloride on survival in cats with CKD has been shown, but benazepril hydrochloride increased the appetite of the cats, particularly in more advanced cases.
After oral administration of benazepril hydrochloride, peak levels of benazepril are attained rapidly (Tmax 0.5 hour in dogs and within 2 hours in cats) and decline quickly as the active substance is partially metabolised by liver enzymes to benazeprilat. The systemic bioavailability is incomplete (~13% in dogs) due to incomplete absorption (38% in dogs, <30% in cats) and first pass metabolism. In dogs, peak benazeprilat concentrations (Cmax of 37.6 ng/ml after a dose of 0.5 mg/kg benazepril hydrochloride) are achieved with a Tmax of 1.25 hours. In cats, peak benazeprilat concentrations (Cmax of 77.0 ng/ml after a dose of 0.5 mg/kg benazepril hydrochloride) are achieved with a Tmax of 2 hours. Benazeprilat concentrations decline biphasically: the initial fast phase (t1/2=1.7 hours in dogs and t1/2=2.4 hours in cats) represents elimination of free drug, while the terminal phase (t1/2=19 hours in dogs and t1/2=29 hours in cats) reflects the release of benazeprilat that was bound to ACE, mainly in the tissues. Benazepril and benazeprilat are extensively bound to plasma proteins (85-90%), and in tissues are found mainly in the liver and kidney. There is no significant difference in the pharmacokinetics of benazeprilat when benazepril hydrochloride is administered to fed or fasted dogs. Repeated administration of benazepril leads to slight bioaccumulation of benazeprilat (R= 1.47 in dogs and R=1.36 in cats with 0.5 mg/kg), steady state being achieved within a few days (4 days in dogs). Benazeprilat is excreted 54% via the biliary and 46% via the urinary route in dogs and 85% via the biliary and 15% via urinary route in cats. The clearance of benazeprilat is not affected in dogs or cats with impaired renal function and therefore no adjustment of dose of the veterinary medicinal product is required in either species in cases of renal insufficiency.