Pharmacodynamic interaction between hydralazine and phenobarbital in normotensive and spontaneously hypertensive rats.

Abstract

Pharmacodynamic interactions between hydralazine (HP) and phenobarbital (PB) were examined in normotensive and hypertensive rats (SHR). The hypotensive effect and the plasma concentration of HP after treatment for 7 d with the combined drugs (5mg/kg of hydralazine hydrochloride and 2.5 mg/kg of PB) or HP alone (5 mg/kg) were measured in comparison with those in a single dose group. The relationship between the hypotensive effect and plasma level of HP was analyzed on the basis of Levy's theory. In normotensive rats, the hypotensive effect was significantly decreased and the elimination of HP from plasma was markedly enhanced after the repeated treatment with the combined drugs, as compared with the results following a single dose. The decrease in the hypotensive effect and enhancement of elimination of HP in SHR, however, were less than those in normotensive rats after repeated treatment. In a single administration of the combined drugs, PB might additively contribute to the hypotensive effect of HP. An analysis of drug interaction according to Levy's theory showed a clear-cut correlation between the plasma level and hypotensive effect of HP (γ>0.968). The hypotensive effect declined linearly with time in each group. In normotensive rats, the extrapolated zerotime intercept (E0) was decreased (77.0 to 53.6 mmHg) and the rate of decline of the hypotensive effect was enhanced after repeated treatment with the combined drugs as compared with that in the single dose group (-7.2 to -10.7 mmHg/h). The rate of decline after repeated treatment with the combined drugs in SHR was slightly smaller than that in the single dose group. The theoretical interpretation of the pharmacokinetic data obtained could account well for the pharmacological effects observed.