Vol. 292, Issue 3, 1087-1093, March 2000

Benazeprilat Disposition and Effect in Dogs Revisited with a Pharmacokinetic/Pharmacodynamic Modeling Approach¹

Pierre-Louis Toutain, Hervé P. Lefebvre and Jon N. King²

Ecole Nationale Vétérinaire de Toulouse, et Institut National de la Recherche Agronomique; Unité Associée de Physiopathologie et Toxicologie Expérimentales, Toulouse, France

The pharmacokinetic disposition of benazeprilat, an angiotensin-converting enzyme (ACE) inhibitor (ACEI), was assessed with a nonlinear binding model in dogs. A single oral benazepril dose, a single i.v. benazeprilat dose, or a daily oral dose of benazepril for 14 consecutive days was administered. The activity of benazeprilat was assessed by measuring plasma ACE inhibition with an ex vivo assay. Benazeprilat data were fitted to equations corresponding to a monocompartmental model with a volume equal to the extracellular space (~0.2 l/kg) in which a fraction of benazeprilat was nonlinearily bound to ACE with both a saturable tissue and nontissue binding. The half-life of benazeprilat elimination determined from this physiologically based model was 39 ± 6 min. The estimated maximal binding capacity of benazeprilat to ACE was ~23.5 nmol/kg, 90% of which was tissular. The estimated equilibrium constant of dissociation (K_d) of benazeprilat to ACE was 2.7 to 4.5 nM. IC₅₀ values were one order of magnitude lower than K_d values (i.e., ~0.27 nM). The nonlinear disposition of benazeprilat raised several issues and it was concluded that the benazeprilat concentration profile was only relevant to definition of an optimal dosage regimen if the appropriate kinetic model was used to interpret the plasma data.