title: Pharmacokinetic/Pharmacodynamic Modeling of Renin-Angiotensin Aldosterone Biomarkers Following Angiotensin-Converting Enzyme (ACE) Inhibition Therapy with Benazepril in Dogs.
abstract: OBJECTIVE
  The objective of this research was to provide a comprehensive description of the effect of benazepril on the dynamics of the renin-angiotensin aldosterone system (RAAS) in dogs.
  
  
  METHODS
  Blood specimens for renin activity (RA), angiotensin II (AII), and aldosterone (ALD) quantitation in plasma were drawn from 12 healthy adult beagle dogs randomly allocated to 2 treatment groups: (i) benazepril 5 mg PO, q24 h (n: 6) and (ii) placebo (n: 6), in a cross-over design. A mechanism-based pharmacokinetic/pharmacodynamic model, which includes the periodic nature of RA, AII, and ALD during placebo treatment and the subsequent changes in dynamics following repeated dosing with benazepril, was developed.
  
  
  RESULTS
  The disposition kinetics of benazepril active metabolite, benazeprilat, was characterized using a saturable binding model to the angiotensin converting enzyme. The modulatory effect of benazeprilat on the RAAS was described using a combination of immediate response models. Our data show that benazepril noticeably influences the dynamics of the renin cascade, resulting in a substantial decrease in AII and ALD, while increasing RA throughout the observation span.
  
  
  CONCLUSIONS
  The model provides a quantitative framework for better understanding the effect of ACE inhibition on the dynamics of the systemic RAAS in dogs.
authors.affiliation: Department of Pharmacology, Leiden-Academic Centre for Drug Research, 2300, Leiden, The Netherlands, jonathan.mochel@novartis.com.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Mochel
authors.forename: Martin
authors.initials: M
authors.lastname: Fink
authors.forename: Mathieu
authors.initials: M
authors.lastname: Peyrou
authors.forename: Antoine
authors.initials: A
authors.lastname: Soubret
authors.forename: Jérôme M
authors.initials: JM
authors.lastname: Giraudel
authors.forename: Meindert
authors.initials: M
authors.lastname: Danhof
mesh_terms: D000284:Administration, Oral; D000450:Aldosterone / Q000097:blood; D000804:Angiotensin II / Q000097:blood; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000818:Animals; D001552:Benzazepines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D015415:Biomarkers / Q000097:blood; D001711:Biotransformation; D004285:Dogs; D005260:Female; D008297:Male; D023421:Models, Animal; D008954:Models, Biological; D017711:Nonlinear Dynamics; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D011485:Protein Binding; D012083:Renin / Q000097:blood; D012084:Renin-Angiotensin System / Q000187:drug effects*
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D001552:Benzazepines; D015415:Biomarkers; D000804:Angiotensin II; D000450:Aldosterone; D007703:Peptidyl-Dipeptidase A; D012083:Renin; C044946:benazepril