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The pharmacokinetic and pharmacodynamic interactions between hydralazine (HP) and furosemide or trimethazidine were determined following single i.v. and repeated (7 d) oral administrations in rats. Both furosemide and trimethazidine caused a significant decrease in the level of plasma protein binding of HP in vivo after i.v. administration. However, in vitro there was no effect on binding. Coadministration of HP and furosemide at lower doses (1.67 mg/kg, i.v. and 5 mg/kg, oral) reduced the hypotensive effect, accompanying the enhanced elimination of HP from plasma after a single i.v. and repeated oral treatment when compared to the result obtained with HP alone. The elimination of HP accelerated by the lower doses of furosemide may be probably due to the increase in renal clearance by the diuretic effect of furosemide. On the contrary, a high dose (10 mg/kg, i.v.) of furosemide temporarily strengthened the hypotensive effect, probably due to the additional hypotensive action of furosemide itself. Trimethazidine (0.75 and 3.75 mg/kg) gave a small increase in the hypotensive effect of HP in spite of the partially enhanced clearance of HP. The pharmacodynamic analysis showed that the hypotensive effect of HP depended upon the plasma HP concentration in each treatment, although the response curves of HP were partly altered by the combined drugs. The present study also suggests a validity of co-administration of HP and diuretics for the therapy of hypertension and heart failure.

Effect of furosemide and trimethazidine on kinetic behavior and hypotensive effect of hydralazine in rats.