Effect of renal insufficiency on the pharmacokinetics and pharmacodynamics of benazepril in cats

Abstract

The effect of renal insufficiency was studied on the pharmacokinetics (PK) and pharmacodynamics (PD) of the angiotensin-converting enzyme (ACE) inhibitor benazepril in cats. The active metabolite of benazepril, benazeprilat, is eliminated principally ( approximately 85%) via biliary excretion in cats. A total of 20 control animals and 32 cats with moderate renal insufficiency induced by partial nephrectomy were used. Assessments were made at steady state after treatment with placebo or benazepril (0.25-2 mg/kg) once daily for a minimum of 10 days. The PK endpoint was the AUC (0-->24 h) of total plasma benazeprilat. The PD endpoints were systolic, diastolic and mean blood pressures (respectively SBP, DBP and MBP) measured by telemetry, and plasma ACE activity, assessed by an ex vivo assay. Renal function was assessed by glomerular filtration rate (GFR), measured by inulin clearance, and plasma creatinine concentrations (1/PCr). As compared with control animals, the renal insufficient cats had a 78% reduction in GFR (0.57 +/- 0.41 mL/min kg), increased plasma creatinine (2.7 +/- 1.0 mg/dL), urea (44.0 +/- 11.9 mg/dL) and ACE activity, and moderately increased blood pressure (SBP 171.8 +/- 5.1 mmHg) (all parameters P < 0.05). Renal insufficient cats receiving benazepril had significantly (P < 0.05) lower SBP, DBP, MBP and ACE, and higher GFR values as compared with placebo-treated animals. There were no significant differences in SBP, DBP, MBP, benazeprilat or ACE values according to the degree of renal insufficiency in cats receiving benazepril. It is concluded that no dose adjustment of benazepril is necessary in cats with moderate renal insufficiency.

Plasma Renin Activity and Aldosterone Concentrations in Hypertensive Cats with and without Azotemia and in Response to Treatment with Amlodipine Besylate

“…Relative or absolute hyperaldosteronism could be a possible cause. Hypertensive cats with naturally occurring CKD and experimentally induced renal insufficiency respond poorly to treatment with angiotensin‐converting enzyme inhibitors (ACEi) 4, 6, 7, 8. The study by Steele and colleagues evaluated the effect of ACEi (benazepril or enalapril) therapy in cats with systemic hypertension and CKD.…”

Effects of Benazepril Hydrochloride in Cats with Experimentally Induced or Spontaneously Occurring Chronic Renal Failure

“…Because ACE inhibitors carry the risk of hypotension and acute reduction in glomerular filtration [23], we chose to increase the dose of BH gradually to the final dose of 1 mg/kg/day, the dose found sufficient to inhibit ACE activity in cats [17,18].…”

“…Of the available ACE inhibitors, BH is different in that it is excreted in urine and bile [45]. Pharmacokinetic studies showed that in cats, up to 85% of benazeprilat, the active metabolite of BH, is eliminated via biliary excretion [18], and repeated oral administrations of BH result in a little accumulation of benazeprilat [17]. Similarly, clearance of plasma benazeprilat was found to increase in dogs with experimentally induced renal insufficiency, while that of enalapril, another ACE inhibitor, was decreased to 40 to 55% [42].…”

“…Similarly, clearance of plasma benazeprilat was found to increase in dogs with experimentally induced renal insufficiency, while that of enalapril, another ACE inhibitor, was decreased to 40 to 55% [42]. Moreover, BH was equally effective to improve systemic blood pressure and glomerular filtration at 0.25 to 2 mg/kg/day in cats with experimentally induced renal insufficiency [7,18]. A recent randomized controlled clinical study demonstrated that benazepril conferred substantial renal benefits to humans with advanced renal insufficiency [14].…”

Angiotensin-Converting Enzyme Inhibitors in Veterinary Medicine

“…In cats, benazeprilat is excreted predominantly (about 85%) by the liver. Similarly, renal dysfunction does not alter benazeprilat pharmacokinetics in this species [9]. One finding from these studies is that, due to the highly complicated pharmacology of ACE inhibitors, it is impossible to predict the effect of renal dysfunction on the disposition of ACE inhibitors only from studies in healthy animals.…”