Plasma angiotensin converting enzyme activity and pharmacokinetics of benazepril and benazeprilat in cats after single and repeated oral administration of benazepril.HCl

Abstract

The plasma pharmacokinetics of benazepril and its active metabolite, benazeprilat, were determined in cats after oral administration of benazepril.HCl at dosages of 0.25, 0.5 and 1.0 mg/kg as a single dose (n = 5 per group) and after once daily application for 8 days (n = 6 per group). Pharmacodynamics were assessed by measurement of plasma angiotensin converting enzyme (ACE) activity. After single administration of benazepril.HCl, maximum benazepril concentrations were recorded at the first sample (2 h) and declined relatively rapidly with an elimination half life (t1/2) of 1.4 h. Highest benazeprilat concentrations were recorded at the first sample (2 h) in most cats and declined biphasically with half lives of each phase of 2.4 and 27.7 h. With repeated administration, plasma benazeprilat concentrations accumulated slightly with accumulation ratios (R) of 1.46, 1.36 and 1.24 for the 0.25, 0.5 and 1.0 mg/kg dosages of benazepril.HCl, respectively (median value of 1.36 for all dosages). All three dosages of benazepril.HCl caused marked inhibition of plasma ACE activity in all cats. The maximum effect (Emax, % inhibition of ACE as compared to baseline) was > or = 98% after single and 100% with repeated administration. The duration of action of benazepril.HCl was long, with > 87% (single) and > 90% (repeat) inhibition of plasma ACE persisting 24 h after dosing. Benazepril.HCl was well tolerated in all animals. Dosages of 0.25-1.0 mg/kg benazepril.HCl once daily are recommended for clinical testing in cats.

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

“…It was assumed that equilibrium conditions existed in both parts of the study, as steady state for both plasma benazeprilat and ACE activity should be reached within 2–3 days with a daily dosage of benazepril in cats (King et al ., 1999).…”

“…We were concerned that this was too few to produce reliable results. Therefore, we reanalysed previously published data in cats (King et al ., 1999) using the Pearson correlation test and found significant positive correlations between AUC values determined using seven points (0, 2, 4, 6, 8, 12 and 24 h) as compared with using six points (0, 2, 6, 12 and 24 h) with a ρ ‐value of 0.98, or using five points (0, 2, 4, 6, 12 and 24 h) with a ρ ‐value of 0.95. Therefore, it was concluded that the AUC values calculated in this study using 5–6 data points were sufficiently robust.…”

“…As is the case with all ACEIs, the PKs of benazeprilat deviate slightly from dose linearity; AUC values are lower than dose‐proportional with higher dosages of benazepril as a result of saturable binding of benazeprilat to ACE (King et al ., 1999; Toutain et al ., 2000b). However, in this study the deviation from linearity for benazeprilat AUC values was minimal and nonsignificant ( P =0.64), and the range of dosages of benazepril.HCl administered was large (0.25–2 mg/kg).…”

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].…”