Synthesis, formulation, and clinical pharmacological evaluation of hydralazine pyruvic acid hydrazone in two healthy volunteers.

Hydralazine pyruvic acid hydrazone [2-(phthalazin-1-yl hydrazono)propionic acid; 1] is a major plasma metabolite of hydralazine in humans. A number of in vitro and animal studies have suggested that this hydrazone may have cardiovascular activity and could account for the prolonged antihypertensive effect of hydralazine in humans in the absence of detectable plasma levels of the parent drug. To study this possibility, the soluble sodium salt of hydralazine pyruvic acid hydrazone (2) was synthesized, its chemical purity and stability was checked, and an intravenous formulation was prepared. Isomeric forms were identified. Doses of 0.3, 0.6, and 1.1 mumol/kg of 2 were administered intravenously to one slow and one heterozygous fast acetylator of sulfamethazine. The slow acetylator received two additional doses of 0.06 and 0.14 mumol/kg. Peak plasma levels of 1 of 18 mumol/L were attained without tachycardia or hypotension in either subject. There was no evidence of nonlinearity in kinetics over the dose range studied and clearance remained constant in both subjects (0.517 +/- 0.033 mL/min/kg in the slow acetylator and 0.744 +/- 0.058 mL/min/kg in the fast acetylator). The distribution of 1 varied unpredictably with dose, and changes were reflected in the terminal half-life (3.47-5.97 h in the slow acetylator and 2.06-5.33 h in the fast acetylator). Only traces of the acetylated metabolite of hydralazine, 3-methyl-s-triazolo[3,4-a]phthalazine (3), were detected in the plasma of the subjects, suggesting that significant metabolism via this route was unlikely. An established and specific assay for hydralazine was further modified to allow measurement of levels as low as 1 nmol/L (0.2 ng/mL).(ABSTRACT TRUNCATED AT 250 WORDS)