The metabolism of the anti-inflammatory drug eterylate in rat, dog and man.

Oral doses of 14C-eterylate were well absorbed by rat and man and excreted mainly in the urine (94% dose by rat in three days and 91% by man in five days). Oral doses to dogs were excreted in similar proportions in both the urine and faeces, although faecal 14C was probably derived in part, from biliary-excreted material. Peak plasma 14C and drug concn. were generally reached between one and three hours after oral doses. In humans, only two metabolites, salicylic acid and 4-acetamido-phenoxyacetic acid, were detected in plasma. The latter was cleared more rapidly than the former and hence plasma salicyclate concn. reached a peak (10.9 and 19.8 micrograms/ml in Subjects 1 and 2, respectively) and initially declined with a half-life of about two-three hours. Plasma 4-acetamidophenoxyacetic acid concn. reached a peak (4.3, 10.0 micrograms/ml, respectively) and declined with a half-life of about one hour. Tissue concn. of 14C were generally greater in dogs than in rats. Highest conc. occurred at three hours in dogs and at one hour in rats. Apart from those in the liver and kidneys, tissue concn. were lower than those in the corresponding plasma. Unchanged drug was not detected in urine or plasma of any species and was rapidly metabolized in human plasma. The major 14C components in human urine were identified as salicyluric acid and 4-acetamidophenoxyacetic acid; minor metabolites were salicylic acid, gentisic acid and paracetamol. These metabolites were also detected in rat urine albeit in different proportions to those in human urine. Dog urine contained less of these metabolites and a major proportion of the 14C was associated with relatively non-polar components. Although salicylic acid and 4-acetamidophenoxyacetic acid were the only major circulating metabolites in man and rat, dog plasma also contained the non-polar urine metabolites.

GLC determination of ticrynafen and its metabolites in urine, serum, and plasma of humans and animals.

A sensitive GLC assay for ticrynafen, a diuretic agent with uricosuric properties, and its two metabolites in urine, serum, and plasma is described. The method employs methylation of carboxylic acid groups and trimethylsilyation of the hydroxyl group on one metabolite that cannot otherwise be separated readily from ticrynafen as a simple methyl ester. Urinary output and serum or plasma levels of ticrynafen and its two metabolites were measured in specimens from human volunteers receiving one 250-mg tablet.

Gas-liquid chromatographic determination of tienilic acid (SKF 62.698) in human plasma and urine.

A gas-liquid chromatographic method is described for the determination of tienilic acid (SKF 62.698), a diuretic with uricosuric properties, in human plasma and urine. The method, which is based on the methylation of the compound, is rapid, specific and sensitive. The lowest level accurately determined is about 50 ng/ml in plasma and 1 mug/ml in urine. The first results from a human volunteer are given.

Short-term oral and dermal toxicity of MCPA and MCPP.

The herbicieds 2-methyl-4-chlorophenoxy acetic acid (MCPA) and 2-(2-methyl-4-chlorophenoxy) propionic acid (MCPP or mecoprop) were tested for 90 days in rats. The compounds were added to the diet at levels of 0, 50, 400, and 3200 ppm. Growth, food intake, mortality, haematology, blood and liver chemistry, organ weights and histopathology were used as criteria. The main effects of both compounds were growth retardation and elevated relative kidney weights at levels of 400 ppm and more. The 50 ppm dose level can be considered as a no-toxic-effect level in the 90-day study. In subacute dermal studies in rabbits during 3 weeks the dosages were 0, 0.5, 1.0 and 2 g MCPA or MCPP per kg body weight. Therafter followed a recovery period of 2 weeks. Growth, mortality, skin reaction, haematology, organ weights (MCPP) and histopathology were recorded and determined. Both compounds caused slight to moderate erythema at all dose levels, whereas elasticity of the skin was decreased. In both experiments the skin returned to normal during the recovery period. Weight loss was observed at all dose levels. In the MCPA experiment high mortality and histopathological changes in the liver, kidneys, spleen and thymus were recorded at the two highest dose levels. The cause of this could have been either the treatment with MCPA or a dysbacteria infection which developed during the experiment. Oral and intraperitoneal acute toxicity of MCPP for the rat were found to be 1210 and 402 mg/kg, respectively. After a single oral or dermal application of MCPA to the rabbit, the compound was excreted unchanged in the urine.