The metabolism of 1-(3-butoxy-2-carbamoyloxypropyl)-5-ethyl-5-phenyl-(1H,3H,5H)-pyrimidine-2,4,6- trione (febarbamate) in the rat has been studied after oral administration. Using high performance liquid chromatography, fifteen metabolites were isolated from urine, purified and identified by MS and NMR spectrometry. Febarbamate was extensively metabolized and only traces of the unchanged compound were found. The oxygen dealkylation and the (omega-1)-hydroxylation of n-butyl chain are the predominant pathways of the biotransformation and lead to the formation of two major metabolites: 1-(2-carbamoyloxy-3-hydroxypropyl)-5-ethyl-5-phenyl-(1H,3H,5H)-pyrimidine-2,4,6,-trione and 1-[3-(3-hydroxybutoxy)-2-carbamoyloxypropyl]-5-ethyl-5-phenyl-(1H,3H,5H)-pyrimidine-2,4,6,-trione. Hydrolytic cleavage of the ester function, the pyrimidine ring opening and p-hydroxylation of phenyl ring play a less important role. The stepwise degradation of n-butyl chain was also observed.
The biotransformation of 1-(3-butoxy-2-carbamoyloxypropyl)-5-ethyl-5-phenyl-(1H,3H,5H)-pyrimidine-2,4,6-trione (febarbamate) has been investigated in man. Human volunteers received a single oral dose of 15 mg/kg febarbamate. Twenty two metabolites found in urine were separated and purified by means of an extraction with Amberlite XAD-2 and the high performance liquid chromatography. Their chemical structures were established with the help of mass and NMR spectral data and by comparison with known standards. The oxygen dealkylation, the penultimate hydroxylation of the n-butyl chain with consecutive oxidation to the ketone and C 4 hydroxylation of the benzene ring lead to the formation of four major metabolites: 1-(2-carbamoyloxy-3-hydroxypropyl)-5-ethyl-5-phenyl-(1H,3H,5H)-pyrimidine-2,4, 6-trione (41.4%), 1-[3-(3-hydroxybutoxy)-2-carbamoyloxypropyl]-5-ethyl-5-phenyl-(1H,3H,5H)-pyrimidine-2,4,6-trione (20.2%), 1-[3-(3-oxobutoxy)-2-carbamoyloxypropyl]-5-ethyl-5-phenyl-(1H,3H,5H)-pyrimidine-2,4,6-trione (11.1%) and 1-(2-carbamoyloxy-3-hydroxypropyl)-5-ethyl-5-(4-hydroxyphenyl)-(1H,3H,5H)-pyrimidine-2,4,6-trione (9.2%). Hydrolysis of the carbamoyloxy group was insignificant, the pyrimidine ring opening and the oxidation of the 5-ethyl group were not observed. Only traces of the parent drug were found.
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