Disposition and metabolism of 3-hydrazino-6-[N,N-bis(2-hydroxyethyl)amino] pyridazine dihydrochloride in man

Abstract

Three healthy volunteers (two men and one woman) were given single oral doses of 14 mg ofl4C-labelled 3-hydrazino-6-[N,N-bis(2-hydroxyethyl)amino pyridazine dihydrochloride, a new anti-hypertensive agent. The drug was absorbed well, and peak levels ofl4C-activity in the plasma, reached after 1.5–2.0 hrs, ranged between 98 and 161 ng eq/ml. The plasma half-lives of total radiocarbon calculated from the decline in the concentration curves between 2 and 8 hrs varied between 1.4 and 2.1 hr. This phase of rapid decline was followed by a second one with a slower rate of disappearance of14C. Approximately 40% of the radioactivity in the whole blood was confined to the plasma. Within 6 days an average of 102% of the administered dose was recovered, 57% being excreted in the urine and 45% in the faeces. Of the total radioactivity excreted in the urine, more than 70% was eliminated within the first 8 hrs. In the 24-hr urine, the radioactivity due to the two identified metabolites, 3-[bis (2-hydroxyethyl)amino] pyridazine and 3-methyl-6-[bis (2-hydroxyethyl)amino] -s-triazole [4,3-b] pyridazine, did not account for more than 28% of the total radioactivity. Moreover, the second metabolite was shown to derive from another one present in the urine in substantial quantity (38%). It cannot be stated with certainty whether or not any unchanged drug was excreted in the urine.