Pharmacokinetics of an active cadralazine metabolite in plasma and blood vessels of spontaneously hypertensive rats.

The plasma and blood vessel (aorta and mesenteric artery) levels of (+/-)-6-[ethyl(2-hydroxypropyl)amino]-3-hydrazinopyridazine (ISF-2405), an active metabolite of cadralazine, were determined and compared with the changes in blood pressure in spontaneously hypertensive rats after single oral administration of cadralazine. The mean plasma level of ISF-2405 reached a maximum at 0.5 h after oral administration of 3 mg/kg of cadralazine, followed by a rapid elimination with a half-life of 1.0 h, whereas the mean aorta level of ISF-2405 reached a maximum at 4 h after dosing, followed by a slow elimination with a half-life of 6.5 h. The mean mesenteric artery levels of ISF-2405 were almost the same as the mean aorta levels over the time investigated. Both patterns of aorta and mesenteric artery levels of ISF-2405 were in good agreement with those of the hypotensive effects. These findings substantiate the assumption that the slow onset and long duration of the pharmacological effect of cadralazine is closely related to the distribution pattern of the active metabolite ISF-2405 in blood vessels, a target tissue of antihypertensive vasodilator drugs.