The epoxide-diol pathway in the metabolism of hexobarbital in rat and man

Abstract

1. In urine of rats treated with hexobarbital, two hitherto unknown metabolites were identified as 1',2'-epoxyhexobarbital and 1,5-dimethylbarbituric acid. The latter was also found in urine of healthy volunteers who had taken hexobarbital orally. 2. The possible metabolite 1',2'-dihydroxyhexobarbital is chemically labile and decomposes readily to 1,5-dimethylbarbituric acid according to a 'retro-aldol type' reaction. Identification of this compound in addition to the epoxide provides evidence for the existence of an epoxide-diol pathway in the metabolism of hexobarbital. 3. Trace amounts of the epoxide were present in urine of rats, whereas it was not detectable in human urine. The total 1,5-dimethylbarbituric acid excreted, as determined by mass fragmentography, amounted to 15 ± 3% of the dose in rat (N=5) and 23±4% of the dose in man (n = 5). 4. Assays were developed for hexobarbital, 3'-hydroxyhexobarbital and 3'-ketohexobarbital in urine, using capillary g.l.c. with nitrogen-selective detection. Total excreted were, respectively, n = 5) of the dose in rats, and n = 5) of the dose for man. 5. 1,5-Dimethyl-5-hydroxybarbituric acid was identified in rat and human urine as an artefact formed by atmospheric oxidation of 1,5-dimethylbarbituric acid.