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J A Timbrell

Publications and source records attributed to J A Timbrell.

At least 73 records · Page 4Linked to original sources
PubMed1984

Hydralazine-induced lupus: is there a toxic metabolic pathway?

The metabolism of hydralazine in a group of slow acetylator patients with the drug-induced lupus syndrome was compared with the metabolism in asymptomatic control subjects. There were no toxicologically significant difference in metabolite excretion between the groups which reached statistical significance, although there were interesting trends. However, the single lupus patient with the rapid acetylator phenotype excreted considerably greater quantities of phthalazinone than control patients and also increased amounts of hydrazine and hydralazine hydrazones. These results and the trends overall are consistent with the hypothesis that the metabolism of hydralazine may indeed be responsible for the drug induced lupus syndrome.

Acetylation↗
PubMed1984

Urinary metabolic profile of isoniazid in patients who develop isoniazid-related liver damage.

The urinary metabolite profile of isoniazid has been studied in patients receiving the drug as therapy for tuberculosis and the profile in patients suffering liver damage due to isoniazid compared with that in control patients. There were no consistent differences between control patients and those suffering liver damage in the excretion of isoniazid metabolites. It may be that susceptibility to the hepatotoxicity of isoniazid is not due to metabolic differences, although a number of other possible explanations are discussed. It is not at present possible to predict which patients will be susceptible from metabolic studies.

Acetylation↗
PubMed1984

Urinary excretion of acetaminophen and its metabolites as studied by proton NMR spectroscopy.

Acetaminophen and its glucuronide, sulfate, N-acetyl-L-cysteinyl, and L-cysteinyl metabolites can be rapidly detected by 1H NMR spectroscopy of intact, untreated human urine. Study of the time course of excretion of these metabolites in five clinically normal men after ingestion of the usual 1-g therapeutic dose of the drug showed that the mean 24-h excretion of the drug and these metabolites as determined by NMR was 77.3% of the dose. Respective relative proportions of the above metabolites were 49.9%, 37.6%, 3.0%, and 9.5% (L-cysteinyl plus free drug). Excretion of some other metabolites in urine, including creatinine, citrate, hippurate, and sarcosine was measured concurrently. Excretion of creatinine and sarcosine was closely correlated.

Acetaminophen↗
PubMed1983

Drug hepatotoxicity.

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Budd-Chiari Syndrome↗
PubMed1982

Studies on hydrazine hepatotoxicity. 1. Pathological findings.

The pathogenesis and factors affecting hydrazine-induced fatty liver have been investigated in rats using histological and ultrastructural examination. A dose of 20 mg hydrazine/kg caused the accumulation of lipid, swelling of mitochondria, and the appearance of microbodies in both periportal and midzonal hepatocytes and in the proximal tubular cells of the kidney. These changes were detectable by light or electron microscopy 24 h after dosing with hydrazine. A dose of 60 mg/kg was the highest dose tolerated for 24 h, but the severity of the fatty liver was similar to that after a dose of 40 mg/kg. The accumulation of lipid droplets and the swelling of mitochondria were detectable by electron microscopy 30 min after dosing, but the accumulation of fat could not be detected by light microscopy until 4 h after dosing. Pretreatment of animals with phenobarbital or piperonyl butoxide respectively reduced and increased the severity of the fatty liver. Pyruvate azine was much less toxic than the parent hydrazine on a molar basis, although some fatty vacuolation was detectable in midzonal hepatocytes.

Animals↗
PubMed1982

Studies on hydrazine hepatotoxicity. 2. Biochemical findings.

Hydrazine causes a dose-related increase in liver triglycerides and in liver weight and causes a decrease in hepatic glutathione. The threshold dose for the toxic effect is around 10 mg/kg, and the optimal effect is seen after a dose of 40 mg/kg. The effect of hydrazine on liver weight and glutathione was detectable within 30 min of dosing, but the elevation of hepatic triglycerides was not detectable until 4 h after dosing. At 24 h after a dose of 60 mg hydrazine/kg, hepatic reduced glutathione was approximately 50% of the control value and triglycerides were about 7 times the normal level. In vitro studies indicated that hydrazine is metabolized by rat liver microsomal enzymes, this being dependent on NADPH and oxygen. Pretreatment of animals with phenobarbital or piperonyl butoxide respectively decreases and increases the hepatotoxicity. Prior depletion of hepatic glutathione by administration of diethyl maleate had no effect on the toxicity. Pyruvate azine, a probable metabolite of hydrazine, is much less toxic than hydrazine itself on a molar basis. These and other results suggest that although hydrazine is metabolized via several routes, the hepatotoxicity may well be due to the parent compound rather than a metabolite.

Animals↗
PubMed1981

Effect of dose on acetylator phenotype distribution of hydralazine.

The effect of dose on acetylator phenotype distribution of hydralazine has been determined, The acetylated metabolites methyltriazolophthalazine (MTP) and 3-hydroxymethyltriazolophthalazine (3-OHMTP) and acid-labile hydralazine (HP) were determined in the 0- to 24-hr urine of patients receiving various doses. The difference between the mean value for the ration 3-OHMTP:HP in the rapid and slow acetylators varied with dose, the greatest difference being after a 200 mg (100 mg twice daily) dose. The distribution of the ratio became less clearly bimodal at lower doses, with overlap between phenotypes occurring at doses of 100 mg (50 mg twice daily) or less. The most effective dose for discriminating between acetylator phenotypes was found to be 200 mg (100 mg twice daily).

Acetylation↗
PubMed1981

Further evidence for an acetylator phenotype difference in the metabolism of hydralazine in man.

1 The 0-24 h urine from hypertensive patients treated with hydralazine (100 mg twice daily) has been analysed by gas chromatography and high pressure liquid chromatography. 2 4-N-Acetylhydrazinophthalazine-1-one (NAcHPZ), s-triazolo [3, 4-a] phthalazine (TP), phthalazinone (PZ) and hydralazine (free, H; acid-labile hydrazones, HH) were detected and assayed. 3 The results indicate that slow acetylators excrete less NAcHPZ and TP than rapid acetylators but more PZ and HH. 4 Free hydralazine was present in low levels and was only detected in some urine samples. 5 The ratios of the metabolites NAcHPZ/HH; TP/HH; NAcHPZ/PZ and PZ/TP are different in the two acetylator phenotypes. 6 It is possible the ratio PZ/TP may be used for determination of acetylator phenotype. 7 It is concluded that hydralazine metabolism is dependent on the acetylator phenotype.

Acetylation↗
PubMed1980

Determination of hydralazine metabolites: 4-hydrazino-phthalazin-1-one and n-acetylhydrazinophthalazin-1-one by gas chromatography and s-triazolo[3,4-alpha]phthalazine and phthalazinone by high-performance liquid chromatography.

Methods are described for the determination of 2-N-acetylhydrazinophthalazin-1-one, 4-hydrazinophthalazin-1-one, phthalazinone and s-triazolo[3,4-alpha]phthalazine in human urine. 4-Hydrazinophthalazin-1-one and 4-N-acetylhydrazinophthalazin-1-one (following acid hydrolysis) are reacted with acetylacetone to give a distinctive pyrazole derivative which can be determined by gas chromatography using a nitrogen-specific detector. Phthalazinone and s-triazolo[3,4-alpha]phthalazine are measured underivatised by high-performance liquid chromatography.

Chromatography, Gas↗
PubMed1980

Polymorphic acetylation of hydralazine.

The acetylation of hydralazine has been studied in hypertensive patients undergoing maintenance therapy with the drug. The patients were acetylator phenotyped with sulfamethazine. Using gas-liquid chromatography and high-pressure liquid chromatography, hydralazine and two of its acetylated metabolites, methyltriazolophthalazine (MTP) and 3-hydroxymethyltriazolophthalazine (HOMTP), have been determined in the 0- to 24-hr urine. The excretion of hydralazine and HOMTP but not MTP was found to be related to the acetylator phenotype. The metabolic ratio HOMTP: hydralazine showed a bimodal distribution and the average ratio for slow acetylators (1.6) was lower than the ratio in rapid acetylators (14.9). It is concluded that hydralazine is polymorphically acetylated in man. The acetylated metabolite HOMTP was not, however, the major metabolite reported previously.

Acetylation↗
PubMed1980

Isoniazid hepatoxicity: the relationship between covalent binding and metabolism in vivo.

The relationship between the hepatotoxicity and metabolism of isoniazid and its metabolites, acetylisoniazid and acetylhydrazine, has been investigated. Toxic doses of acetylisoniazid and acetylhydrazine, radiolabeled in the acetyl group, were found to bind covalently to liver protein in vivo. This binding was mediated by the microsomal enzyme system as indicated by the effects of pretreatments altering the activity of these enzymes. Metabolic studies revealed that the pretreatments increased the metabolism of the acetylhydrazine moiety of acetyl-labeled acetylisoniazid and of acetylhydrazine itself by the microsomal enzyme system. Pretreatment with the acyl amidase inhibitor, bis-p-nitrophenyl phosphate, inhibited the hydrolysis of acetylisoniazid to isonicotinic acid plus acetylhydrazine and concomitantly decreased the covalent binding of acetyl-labeled acetylisoniazid. The changes in the metabolism of isoniazid, acetylisoniazid and acetylhydrazine effected by various pretreatments paralleled changes in the severity of the hepatic necrosis caused by the compounds. These results strongly suggest that acetylhydrazine is the metabolite responsible for the hepatic necrosis caused by isoniazid and that mirosomal metabolism of acetylhydrazine in vivo leads to the production of a reactive acylating species capable of reacting covalently with tissue macromolecules.

Acetylation↗
PubMed1979

Identification and quantitation of hydrazine in the urine of patients treated with hydralazine.

Hydrazine has been identified by gas chromatography-mass spectrometry in the 0- to 24-hr urine of patients administered hydralazine. With a specific gas chromatographic assay procedure, the amount of hydrazine in the 0- to 24-hr urine was determined in patients treated with various doses of hydralazine. The amount of hydrazine detected in the urine was greater in the slow acetylator phenotype than in the rapid acetylator phenotype. Studies indicated that hydrazine was not produced by chemical breakdown of hydralazine or its known metabolites in urine and therefore was unlikely to be a urinary artefact formed by chemical decomposition in the urine.

Acetylation↗