[Modeling of the relation between plasma concentration of the active metabolite of perindopril and inhibition of the activity of plasma converting enzyme in healthy volunteers].
The purpose of this study was to investigate the relationship between plasma concentration (Cp) of perindoprilat (P), the active metabolite of perindopril, and plasma converting enzyme activity (CEA) after a single oral administration of perindopril. CEA and Cp were investigated before, and, 1, 2, 3, 4, 6, 8, 10, 24 and 48 hours after a random administration of a placebo or 4, 8, 16 mg perindopril in a double-blind and crossover study performed in 6 healthy male volunteers. Effect on CEA was expressed as the percentage of inhibition of pretreatment value (CEA0): CEI = 100 (CEA0 = CEA)/CEA0. The CEI-Cp relationship was non linear and displayed an hysteresis loop. Following Sheiner et al. (Clin Pharmacol Ther, 1979; 25: 358-71), we used an effect compartment in which drug dissipation is governed by a first-order rate constant keo. Concentration of P in the effect compartment (Ce) was related to CEI by the Hill equation CEI = 100 Emax Cen/(EC50n + Cen), where Emax (expressed as a percentage) is the theoretical maximum effect, EC50 the Ce which produces 50 p. 100 of Emax, and n the Hill coefficient. Pharmacodynamic parameters were estimated by the non parametric approach proposed by Unadkat et al. (Clin Pharmacol Ther, 1986; 40: 86-93). The Hill equation was fitted to the data for 3 different values of n: 1, 2, and 3.


RESULTS
for all the 3 doses, the best curve fitting was achieved for n = 1 or 2. We obtained keo = 0.60 +/- 0.30 h-1 (mean +/- s.d.), Emax = 90 +/- 10 p. 100, EC50 = 1.30 +/- 0.95 ng/ml.(ABSTRACT TRUNCATED AT 250 WORDS)
Bellissant
E
E
Service de pharmacologie clinique, hôpital de Bicêtre, Le Kremlin-Bicêtre.
Chau
N P
NP
Thuillez
C
C
Giudicelli
J F
JF
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004789:Enzyme Activation; D006801:Humans; D007211:Indoles / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D008954:Models, Biological; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D020913:Perindopril
D000806:Angiotensin-Converting Enzyme Inhibitors; D007211:Indoles; D007703:Peptidyl-Dipeptidase A; D020913:Perindopril
Modélisation de la relation entre concentration plasmatique du métabolite actif du perindopril et inhibition de l'activité de l'enzyme de conversion plasmatique chez le volontaire sain.