Hypotensive effect of the hydralazine--acetone hydrazone in conscious rabbits: evidence for its back-conversion to hydralazine in vivo.
The hydralazine--acetone hydrazone (HAH) has previously been identified as a metabolite of hydralazine (H) in humans. We compared the hypotensive effects of HAH and H in groups of hypertensive rabbits. Both compounds caused a dose-dependent depressor response, with a potency ratio of HAH to H of approximately 0.2. Upon their intravenous administration to anephric rabbits, both H and HAH produced sustained concentrations in plasma of the H-pyruvic acid hydrazone, demonstrating that back-conversion of HAH to H occurred in vivo. We conclude that HAH is hydrolyzed in vivo to yield parent H. The levels of the H-metabolite, the pyruvic acid hydrazone, suggest that the hypotensive effect of HAH could be explained entirely by generation of H in vivo. This combined pharmacokinetic and pharmacodynamic approach can be applied to other H-hydrazones to evaluate their backconversion to H in vivo.
D000818:Animals; D000959:Antihypertensive Agents / Q000378:metabolism*; D001794:Blood Pressure / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D006830:Hydralazine / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D006977:Hypertension, Renal / Q000188:drug therapy; D007700:Kinetics; D008297:Male; D011817:Rabbits
D000959:Antihypertensive Agents; D006830:Hydralazine; C034601:hydralazine acetone hydrazone; C023497:hydralazine pyruvic acid hydrazone