Relationship between plasma concentration and antihypertensive effect of the dihydropyridine calcium antagonist, benidipine, in rats

Although benidipine hydrochloride, a hydrophobic and weakly cationic dihydropyridine calcium antagonist, has slow onset but long-lasting anti-hypertensive effect in experimental animals and man, after administration it rapidly disappears from the plasma. Correlation of the plasma concentration with reduction in blood pressure has been investigated in spontaneously hypertensive rats, and concentrations in the mesenteric artery were compared with those in plasma after oral and intravenous administration of benidipine to rats. After oral administration of benidipine to spontaneously hypertensive rats, the fall in blood pressure showed an anti-clock hysteresis phenomenon. Using concomitant analysis, plasma concentrations and anti-hypertensive activity could both be closely fitted to a one-compartment open model and the effect compartment for the pharmacological activity of benidipine could be described by a Hill equation. Concentrations in the mesenteric artery increased rapidly and then declined more slowly than in plasma. The mean residence time of benidipine in the mesenteric artery corresponded closely to the reciprocal of the rate constant for elimination of benidipine from the effect compartment. From these results it seems that benidipine is retained longer in the plasma membrane, an effective site, because of its physicochemical properties, and thus shows a more sustained anti-hypertensive effect than would be predicted from its disposition in plasma.