Pharmacokinetic/pharmacodynamic modeling of benazepril and benazeprilat after administration of intravenous and oral doses of benazepril in healthy horses

• Published in: Research in veterinary science 2017-10, Vol.114, p.117-122
• Main Authors: Serrano-Rodríguez, Juan Manuel, Gómez-Díez, Manuel, Esgueva, María, Castejón-Riber, Cristina, Mena-Bravo, Antonio, Priego-Capote, Feliciano, Ayala, Nahúm, Caballero, Juan Manuel Serrano, Muñoz, Ana
• Format: Article
• Language: English
• Subjects: Administration, Intravenous; Administration, Oral; Angiotensin-converting enzyme inhibitors; Angiotensin-Converting Enzyme Inhibitors - administration & dosage; Angiotensin-Converting Enzyme Inhibitors - blood; Angiotensin-Converting Enzyme Inhibitors - metabolism; Angiotensin-Converting Enzyme Inhibitors - pharmacokinetics; Animals; Benazepril; Benazeprilat; Benzazepines - blood; Benzazepines - metabolism; Benzazepines - pharmacokinetics; Benzazepines - pharmacology; Bioavailability; Biological Availability; Blood; Cardiomyopathy; Conversion; Cross-Over Studies; Drug dosages; Enzymes; Horses; Horses - blood; Horses - metabolism; Hypertension; Intravenous administration; Liquid chromatography; Male; Mass spectrometry; Mass spectroscopy; Medical research; Peptidyl-dipeptidase A; Pharmacodynamics; Pharmacokinetic-pharmacodynamic; Pharmacokinetics; Pharmacology; Spectrophotometry; Studies; Veterinary medicine
• ISSN: 0034-5288; 1532-2661
• DOI: 10.1016/j.rvsc.2017.03.016

Pharmacokinetic and pharmacodynamic (PK/PD) properties of the angiotensin-converting enzyme inhibitor (ACEI) benazeprilat have not been evaluated in horses. This study was designed to establish PK profiles for benazepril and benazeprilat after intravenous (IV) and oral (PO) administration of benazepril using a PK/PD model. This study also aims to determine the effects of benazeprilat on serum angiotensin converting enzyme (ACE), selecting the most appropriate dose that suppresses ACE activity. Six healthy horses in a crossover design received IV benazepril at 0.50mg/kg and PO at doses 0 (placebo), 0.25, 0.50 and 1.00mg/kg. Blood pressures (BP) were measured and blood samples were obtained at different times in order to measure serum drug concentrations and serum ACE activity, using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and spectrophotometry, respectively. Systemic bioavailability of benazeprilat after PO benazepril was 3–4%. Maximum ACE inhibitions from baseline were 99.63% (IV benazepril), 6.77% (placebo) and 78.91%, 85.74% and 89.51% (for the three PO benazepril doses). Significant differences in BP were not found. Although oral availability was low, benazeprilat 1.00mg/kg, reached sufficient serum concentrations to induce long lasting serum ACE inhibitions (between 88 and 50%) for the first 48h. Additional research on benazepril administration in equine patients is indicated. •Angiotensin converting enzyme inhibitor benazeprilat was evaluated in horses after different IV and PO doses of benazepril.•Pharmacokinetics and pharmacodynamics relationships were obtained and investigated.•Oral bioavailability of benazeprilat after PO benazepril was low.•Benazepril doses of 0.50 and 1.00mg/kg had sufficient bioconversion to benazeprilat to induce ACE inhibitions near to 88%.•Further works with different doses or formulations in equine patients should be investigated.