Benazeprilat disposition and effect in dogs revisited with a pharmacokinetic/pharmacodynamic modeling approach

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 inhibitio n with an ex vivo assay. Benazeprilat data were fitted to equations corresp onding to a monocompartmental model with a volume equal to the extracellula r space (similar to 0.2 l/kg) in which a fraction of benazeprilat was nonli nearily bound to ACE with both a saturable tissue and nontissue binding. Th e half-life of benazeprilat elimination determined from this physiologicall y based model was 39 +/- 6 min. The estimated maximal binding capacity of b enazeprilat to ACE was similar to 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., similar to 0.27 nM). The nonlinear disposition of benazep rilat raised several issues and it was concluded that the benazeprilat conc entration profile was only relevant to definition of an optimal dosage regi men if the appropriate kinetic model was used to interpret the plasma data.