Pharmacokinetic/pharmacodynamic modelling of the disposition and effect of benazepril and benazeprilat in cats

Abstract

The disposition and effect of benazepril and its active metabolite, benazeprilat, were evaluated in cats using a pharmacokinetic/pharmacodynamic model. Cats received single 1 mg/kg doses of intravenous 14C-benazeprilat and oral 14C-benazepril.HCl, and single and repeat (eight daily) oral administrations of 0.25, 0.5 and 1.0 mg/kg nonlabelled benazepril.HCl. The pharmacokinetic endpoints were plasma concentrations of benazepril and benazeprilat, and recovery of radioactivity in faeces and urine. The pharmacodynamic endpoint was plasma angiotensin-converting enzyme (ACE) activity. Benazeprilat data were fitted to an equation corresponding to a single-compartment model with a volume equal to the blood space (Vc = 0.093 L/kg). Within this space, benazeprilat was bound nonlinearly to ACE, which was mainly tissular (89.4%) rather than circulating (10.6%). Free benazeprilat was eliminated quickly from the central compartment (t1/2 approximately 1.0 h; Cl approximately 0.125 L/kg/h), elimination being principally biliary ( approximately 85%) rather than urinary ( approximately 15%). Nevertheless, inhibition of ACE was long-lasting (t1/2 16-23 h) due to high affinity binding of benazeprilat to ACE (Kd approximately 3.5 mmol/L, IC50 approximately 4.3 mmol/L). Simulations using the model predict a lack of proportionality between dose of benazepril, plasma benazeprilat concentrations and effect due to the nonlinear binding of benazeprilat to ACE. For example, increasing the dose of benazepril (e.g. above 0.125 mg/kg q24 h) produced only small incremental inhibition of ACE (either peak effect or duration of action).