J. Roberts, G. P. Warwick
Jul 1, 1958
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Influential Citations
65
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Journal
Biochemical Pharmacology
Abstract
Abstract The metabolic fate in the rat of 14 C-ethyl methanesulphonate (1), a growth-inhibitive (radiomimetic) alkylating agent, was studied. Thirty-four per cent of the radioactivity is exhaled as carbon dioxide during the first 24 hr after intraperitoneal injection of the compound. Comparison of the rates of exhalation of carbon dioxide following injection of ethyl methanesulphonate and radioactive ethanol suggests that in the former case carbon dioxide is derived from ethanol formed by hydrolysis of the drug at a rate comparable to that which occurs in water at 37°. Approximately 20 per cent of the injected radioactivity is excreted in the urine during three days after injection. While a number of radioactive metabolites are present in the urine, almost all the radioactivity is incorporated in N-acetyl-S-ethylcysteine and other conjugates or derivatives of S-ethylcysteine. This was demonstrated by comparing autoradiographs of chromatograms of urine obtained after injection of 14 C-ethyl methanesulphonate and 14 C-S-ethylcysteine. The nature of some of the metabolites is discussed. A small quantity of radioactive urea in the urine could have been derived from ethanol. A negligible quantity of radioactivity appeared in the faeces. Methyl methanesulphonate and propyl methanesulphonate have also been shown to be excreted as derivatives of the corresponding alkylated cysteines. S-ethylglutathione has been shown to be converted in the rat to derivatives of S-ethylcysteine, evidence to suggest that S-ethylglutathione and S-alkylated proteins may be intermediates in the formation of S-ethylcysteine conjugates from ethyl methanesulphonate. The relevance of the findings in relation to the pharmacological properties of the alkylating agents in general is discussed.