RT Journal Article
SR Electronic
T1 Benazeprilat Disposition and Effect in Dogs Revisited with a Pharmacokinetic/Pharmacodynamic Modeling Approach
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 1087
OP 1093
VO 292
IS 3
A1 Pierre-Louis Toutain
A1 Hervé P. Lefebvre
A1 Jon N. King
YR 2000
UL http://jpet.aspetjournals.org/content/292/3/1087.abstract
AB 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 (Kd) of benazeprilat to ACE was 2.7 to 4.5 nM. IC50 values were one order of magnitude lower thanKd 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. The American Society for Pharmacology and Experimental Therapeutics