Biomedical subjects

J A Timbrell

Publications and source records attributed to J A Timbrell.

94 records · Page 6Linked to original sources

PubMedDate not supplied

Factors affecting the metabolism of [14C]acetylhydrazine in rats.

Some factors affecting the metabolism of the potent hepatotoxin, acetylhydrazine, were studied in rats. After ip administration of [14C]acetylhydrazine, 36% and 38% of the dose was recovered in the urine and as 14CO2, respectively. The major urinary metabolites were diacetylhydrazine and the pyruvic acid and alpha-oxoglutaric acid acetylhydrazones. The acetylation of acetylhydrazine to diacetylhydrazine was found to be dose-dependent and to be inhibited by coadministered isoniazid and p-aminosalicylic acid. Coadministered acetylisoniazid had no effect on acetylation. The proportion of acetylhydrazine recovered as 14CO2 presumably reflects the amount metabolized by the microsomal oxidation pathway, thought to be responsible for the toxicity, and also possibly by hydrolysis to acetate and hydrazine. This latter pathway could not be confirmed, as only a small proportion of hydrazine administered to rats was recovered. The inhibition of acetylation by p-aminosalicyclic acid, but not isoniazid, significantly increased the excretion of 14CO2, suggesting that isoniazid may also inhibit a pathway resulting in the production of 14CO2. These results indicate that the metabolism and hepatotoxicity of acetylhydrazine may be different when it is produced as a metabolite of isoniazid than when it is given alone.

Acetylation↗

PubMedDate not supplied

Studies on the effects of isoniazid on acetylhydrazine metabolism in vivo and in vitro.

The interaction of isoniazid with its hepatotoxic metabolite acetylhydrazine has been studied. In vitro, isoniazid at a concentration of 0.5 mM was found to inhibit the microsomal metabolism of acetylhydrazine to a reactive acylating species. In vivo, however, coadministered isoniazid inhibited the acetylation to diacetylhydrazine and concomitantly increased the microsomal metabolism of 14C-acetylhydrazine to a reactive intermediate which covalently bound to liver macromolecules. Comparison of urinary metabolites of isoniazid at two dose levels indicated that acetylation of acetylhydrazine produced as a metabolite may be inhibited by the parent drug.

Acetylation↗

PubMedDate not supplied

Enzyme-mediated covalent binding of hydralazine to rat liver microsomes.

Hydralazine was metabolized in vitro to a reactive metabolite(s) which bound to microsomal protein. The binding was dependent on mixed function oxidase activity, was proportional to time and microsomal protein concentration, and was not removed by acid washing. The apparent Km was 3.55 X 10(-5) M and the Vmax was 0.342 nmol/mg protein/min. Binding was inhibited by carbon monoxide and required oxygen and enzyme activity. Microsomes from animals pretreated with 3-methylcholanthrene showed a slight but significant increase in covalently bound hydralazine metabolite(s) whereas piperonyl butoxide treatment significantly reduced this binding. Glutathione, cysteine, and N-acetylcysteine all reduced the binding when added to incubations. Therefore, hydralazine is metabolized by the microsomal enzymes to a metabolite(s) capable of reacting covalently with cellular macromolecules.

Animals↗

PubMedDate not supplied

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.

Animals↗