Pharmacokinetics of cadralazine in hypertensive patients

Pharmacokinetics of cadralazine, urinary recovery of its putative active metabolite 3-hydrazino-6-aminopiridazine derivative (ISF 2405) and clinical effects were assessed in a placebo-controlled trial in 8 hypertensive in-patients, after acute oral administration of cadralazine. After a 2-week placebo-washout period, the protocol envisaged two consecutive days of monitoring of blood pressure and heart rate. On the first day a placebo tablet was given (9 am), while on the second day patients received a 30 mg cadralazine tablet in single-blind conditions. Blood and urine samples were obtained during the active drug day until 12 h after administration. Concentration of cadralazine in plasma and urine was detected by a specific HPLC method, while the metabolite ISF 2405 was detected in urine by a GC-MS method. Cadralazine caused gradual and long-lasting pressure decrease, statistically significant in comparison to placebo between 3 and 12 hours from drug intake, accompanied by a significant increase in heart rate. Cadralazine by oral route was promptly absorbed with a mean peak time of 1.3 h. Thereafter it followed a monoexponential decay curve, with a plasma half life of 3.1 h. The relative different bioavailability of oral cadralazine among patients was not correlated with cardiovascular changes. Urine recovery of unchanged drug after 12 h was high, reaching 67.3%, while concentration of metabolite ISF 2405 was about 1/1000 of parent compound.