Pharmacokinetics of formation and excretion of some metabolites of hydralazine and their hypotensive effect in rats.
To evaluate the hypotensive effect and pharmacokinetic properties of some metabolites of hydralazine (HP), blood pressure and plasma concentrations after the i.v. or i.p. administration of HP pyruvate, alpha-ketoglutarate and acetone hydrazones and 3-methyl-s-triazolo[3,4a]phthalazine were estimated in normotensive rats, in addition to in vitro kinetic studies of the formation and decomposition. All the hydrazones studied had an effective hypotensive effect after a high dosing (10 mg/kg); however, their potency was much smaller than that of HP, when plasma-free concentration-response curves were compared. 3-methyl-s-triazolo[3,4a]phthalazine had no hypotensive effect at the same dose. Virtually no effective quantities of HP were generated in plasma after i.v. injection of these hydrazones (10 mg/kg) except for HP acetone hydrazone although a specific and sensitive analytical method for HP was used. The metabolites had larger elimination rate constants and smaller apparent distribution volumes than those of HP. Hydrazones in vitro were formed according to a second-order rate kinetics from HP and various keto acids or ketone at pH 7.4 and 37 degrees C, and these compounds were partly decomposed under the same conditions. Of the metabolites HP pyruvic acid hydrazone was the most readily formed and relatively stable hydrazone, whereas HP acetone hydrazone was unstable. The present results indicate that the contribution of the hydrazones to the vasodepressor properties of HP is only partial or negligible and that the hypotensive effect after dosing of HP is related mainly to its free concentration.
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D006830:Hydralazine / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D006835:Hydrazones / Q000097:blood / Q000494:pharmacology; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D010793:Phthalazines / Q000097:blood / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D006835:Hydrazones; D010793:Phthalazines; C008508:3-methyl-s-triazolo(3,4-a)phthalazine; D006830:Hydralazine