title: Dose-effect relationship of perindopril 10, 14 and 20mg assessed by urine and plasma AcSDKP levels in mildly sodium-depleted healthy volunteers.
abstract: BACKGROUND
  We describe a pharmacodynamic study of the dose-effect relationship of perindopril arginine at 10, 14, and 20mg with in vivo angiotensin-converting enzyme (ACE) activity, assessed by urine and plasma AcSDKP levels, as well as the effect on plasma active renin concentrations and blood pressure.
  
  
  METHODS
  This randomized, double-blind, four-period, crossover study involved single-dose administration of perindopril arginine (10, 14, and 20mg or placebo) to 32 healthy male normotensive mildly sodium-depleted volunteers. Blood and urine were collected over 48h for AcSDKP, ACE activity, and plasma active renin measurements.
  
  
  RESULTS
  There were dose-related increases in urinary AcSDKP excretion and plasma AcSDKP concentration after administration of perindopril, with significant between-period differences (estimate of the median difference in urinary excretion over 48h of AcSDKP, 49.1 [95% CI: 15.3-82.0] nmol for 14 versus 10mg, and 73.2 [95% CI: 44.9-106.3] nmol for 20 versus 14mg). Consequently, a dose-dependent increase in plasma active renin concentration was observed. Even though each dose of perindopril 10 to 20mg was associated with a significant 24-h ambulatory blood pressure reduction versus placebo, no dose-dependency was detected in these normotensive subjects.
  
  
  CONCLUSIONS
  Administration of perindopril arginine 10, 14, or 20mg to mildly sodium-depleted healthy volunteers is associated with a dose-dependent inhibition of in vivo ACE activity with significant between-dose differences. This effect was associated with a dose-dependent increase in plasma active renin concentration, indicating a dose-dependent blockade of the renin angiotensin system.
authors: Hôpital Européen Georges Pompidou, Centre d'Investigations Cliniques, F-75015 Paris, France.
authors: Matthieu
authors: M
authors: Monge
authors: Hôpital Européen Georges Pompidou, Centre d'Investigations Cliniques, F-75015 Paris, France.
authors: Valérie
authors: V
authors: Paquet
authors: INSERM, CIC1418, F-75015 Paris, France.
authors: Damien
authors: D
authors: Bergerot
authors: Hôpital Européen Georges Pompidou, Centre d'Investigations Cliniques, F-75015 Paris, France; Université Paris-Descartes, F-75006 Paris, France.
authors: Valentina
authors: V
authors: Zhygalina
authors: Hôpital Européen Georges Pompidou, Centre d'Investigations Cliniques, F-75015 Paris, France; INSERM, CIC1418, F-75015 Paris, France; Université Paris-Descartes, F-75006 Paris, France. Electronic address: anne.blanchard@aphp.fr.
authors: Anne
authors: A
authors: Blanchard
mesh_terms: D000293:Adolescent; D000328:Adult; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D064368:Healthy Volunteers; D006801:Humans; D007010:Hyponatremia / Q000097:blood* / Q000652:urine*; D008297:Male; D009842:Oligopeptides / Q000097:blood* / Q000652:urine*; D020913:Perindopril / Q000494:pharmacology*; D012982:Sodium, Dietary / Q000008:administration & dosage / Q000037:antagonists & inhibitors; D055815:Young Adult
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D009842:Oligopeptides; D012982:Sodium, Dietary; C058504:goralatide; D020913:Perindopril
keywords: ACE inhibition; AcSDKP; Perindopril arginine; Pharmacodynamics; Phase 1 study