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

Abstract

1. 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.

2. 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 salicylate concn. reached a peak (10.9 and 19.8 μg/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 μg/ml, respectively) and declined with a half-life of about one hour.

3. 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 concoccurred were lower than those in the corresponding plasma.

4. 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.