Influence of acetylator status on the haemodynamic effects and pharmacokinetics of cadralazine in healthy subjects.
1. Cadralazine is a new antihypertensive agent which causes peripheral vasodilation, probably mediated by a hydrazinopyridazine metabolite. 2. The possible influence of acetylator status on the pharmacokinetics and haemodynamics of the drug was studied in six fast and six slow acetylators over a period of 24 h after administration of a single 10 mg oral dose. 3. There were no differences between the two groups in AUC and Cmax values of cadralazine and apparent metabolite, the latter defined as the sum of the free and conjugated hydrazinopyridazine. Peak plasma concentrations of these compounds were reached after 1 h. Thereafter, the concentration of the metabolite declined more slowly than that of cadralazine. 4. No effects on blood pressure were noted. Changes in heart rate and plasma renin were delayed by 3-5 h with respect to the time-course of drug and metabolite in plasma; maximum responses occurred at 4-6 h after drug administration. The extent of the increase in plasma renin activity was slightly greater in slow than in fast acetylators, but the difference was not significant statistically.
Pharmaceutical Research and Development Department, CIBA-GEIGY Limited, Basle, Switzerland.
P
P
Brunel
J B
JB
Lecaillon
T T
TT
Guyene
P
P
Imhof
J
J
Ménard
D000107:Acetylation; D000328:Adult; D000959:Antihypertensive Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D005542:Forearm / Q000098:blood supply; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011724:Pyridazines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D012039:Regional Blood Flow / Q000187:drug effects; D012083:Renin / Q000097:blood; D013318:Stroke Volume / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
D000959:Antihypertensive Agents; D011724:Pyridazines; C055809:ISF 2405; C031877:cadralazine; D012083:Renin