Abstract
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.
Footnotes
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Send reprint requests to: P.-L. Toutain, Ecole Nationale Vétérinaire de Toulouse, Laboratoire de Physiologie, 23, chemin des Capelles, 31076 Toulouse Cedex, France. E-mail:pl.toutain{at}envt.fr
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↵1 This work was supported by Novartis Santé Animale, Case postale, CH-4002 Bâle, Switzerland.
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↵2 Current address: Novartis Santé Animale, Case Postale, CH-4002 Bâle, Switzerland.
- Abbreviations:
- ACE
- angiotensin-converting enzyme
- ACEI
- ACE inhibitor
- AUC
- area under the plasma concentration curve
- fcirc
- circulating fraction of ACE
- Received May 20, 1999.
- Accepted December 2, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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