Pharmacokinetic-pharmacodynamic model relating zabiciprilat plasma concentrations to brachial and femoral haemodynamic effects in normotensive volunteers.
OBJECTIVE
To investigate, in healthy volunteers, the relationships between the plasma concentrations (C, ng ml(-1)) of zabiciprilat, the active metabolite of the angiotensin I-converting enzyme inhibitor (ACEI) zabicipril, and the effects (E) induced on plasma converting enzyme activity (PCEA, nmol ml(-1) min(-1)), brachial and femoral artery flows (BAF, FAF, ml min(-1)), and brachial and femoral vascular resistances (BVR, FVR, mmHg x s ml(-1)) after a single oral administration of two doses (0.5 and 2.5 mg) of zabicipril.


METHODS
The study was placebo-controlled, randomized, double-blind and crossover. E was related to C by the Hill model, E = Emax x Cgamma/(CE50gamma + Cgamma), fitted to the data of both doses simultaneously.


RESULTS
We obtained (mean +/- s.d.) Emax = -99 +/- 1%, CE50 = 2.2 +/- 1.0 ng ml(-1) and gamma = 1.0 +/- 0.4 for PCEA, Emax = 55 +/- 26 ml min(-1), CE50 = 5.1 +/- 4.0 ng ml(-1) and gamma = 2.4 +/- 1.6 for BAF, and Emax = -45 +/- 10%, CE50 = 2.0 +/- 1.3 ng ml(-1) and gamma = 2.3 +/- 1.4 for BVR. The parameters obtained for FAF and FVR were similar to those obtained for BAF and BVR, respectively. The CE95 (C required to induce 95% of Emax) varies from 7 to 17 ng ml(-1) for haemodynamic effects.


CONCLUSIONS
As zabiciprilat peak plasma concentrations average 20 ng ml(-1) after the 2.5 mg dose of zabicipril, this dose of the drug should be sufficient to induce optimal haemodynamic effects.
Bellissant
E
E
Service de Pharmacologie Clinique, Hôpital de Bicêtre, Le Kremlin-Bicêtre, France.
Giudicelli
J F
JF
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects*; D001916:Brachial Artery; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004347:Drug Interactions; D005263:Femoral Artery; D006801:Humans; D008297:Male; D008954:Models, Biological; D010919:Placebos; D012039:Regional Blood Flow / Q000187:drug effects; D014655:Vascular Resistance / Q000187:drug effects
D000806:Angiotensin-Converting Enzyme Inhibitors; D019086:Bridged Bicyclo Compounds, Heterocyclic; D010919:Placebos; C067839:zabiciprilat; C065499:zabicipril