Studies on the in vivo metabolism of hydralazine in the rat.

A single dose of [1-14C]hydralazine is extensively metabolized in the rat as no unchanged drug is excreted in the urine, the major route of elimination of the drug. However, only a small proportion of the dose could be accounted for as known metabolites. The lack of expired 14CO2 suggests that the phthalazine ring is metabolically stable. The metabolites were qualitatively but not quantitatively similar to those excreted by human subjects. The three major urinary metabolites were found to be 3-methyl-s-triazolo[3,4a] phthalazine and acid-labile conjugates of hydralazine and 1-hydrazinophthalazin-4-one. There were also small amounts of s-triazolo[3,4-a]-phthalazine, 3-hydroxymethyl-s-triazolo[3,4-a]-phthalazine, hydrazine, and phthalazin-1-one. Induction of the microsomal enzymes by pretreatment with 3-methylcholanthrene reduced the excretion of the acetylated metabolite 3-methyl-s-triazolo[3,4-a]phthalazine, of conjugates of hydralazine and 1-hydrazinophthalazin-4-one. Pretreatment with phenobarbital reduced excretion of 3-methyl-s-triazolo[3,4-a]phthalazine. Conversely, inhibition of the microsomal enzymes by pretreatment with piperonyl butoxide increased the excretion of 3-methyl-s-triazolo[3,4-a]phthalazine and decreased the excretion of 1-hydrazinophthalazin-4-one conjugates. [14C]Hydralazine or a metabolite was covalently bound to tissue protein, particularly in the aorta, lungs, and spleen. Induction of the microsomal enzymes with 3-methylcholanthrene reduced and inhibition of the microsomal enzymes increased the binding to the aorta. In conclusion, the covalent binding of [14C]hydralazine or a metabolite to protein does not appear to be mediated by the microsomal enzymes in the rat and the metabolism of hydralazine in the rat shows considerable quantitative differences from that in man.