The metabolic fate of 1',2'-epoxyhexobarbital in the rat.

1. In urine of rats treated with 1',2'-epoxyhexobarbital, unchanged compound and six metabolites were identified: 1,5-dimethylbarbituric acid, which is the end product of an epoxide-diol pathway, two stereochemically different 3'-hydroxy-1',2'-epoxyhexobarbitals, a hydroxyfuropyrimidine, 3'-hydroxyhexobarbital and 3'-ketohexobarbital. 2. The analytical methods used were based on capillary g.l.c. with nitrogen-selective or mass spectrometric detection. Identification was by electron impact and chemical ionization mass spectrometry. All the reference compounds needed for comparison were synthesized. 3. The mean plasma elimination half-life of 1',2'-epoxyhexobarbital after intra-arterial administration to the rat was 13.7 +/- 1.5 min (mean +/-S.D.; n = 3). A total body clearance of 35.2 +/- 9.6 ml/min (mean +/- S.D.) was calculated, which includes renal clearance of unchanged epoxide. 4. In rat liver microsomal preparations it was demonstrated that 1',2'-epoxyhexobarbital is hydrated by epoxide hydratase. With 1 mM 1,1,1,-trichloropropene-2,3-oxide (TCPO) this enzymic reaction could be inhibited completely. 5. On administration of the individual metabolites of the epoxide to rats, no evidence was found for their possible intermediacy in the formation of 3'-hydroxy- or 3'-ketohexobarbital, which are major metabolites of hexobarbital.

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

1. In urine of rats given vinylbital (5-vinyl-5-(1'-methylbutyl)barbituric acid) i.p., unchanged vinylbital and its devinylated metabolite, 5-(1'-methylbutyl)barbituric acid, were identified. Rats synthetic 1',2'-epoxyvinylbital excreted the same compound as a major metabolite. No unchanged epoxide, nor 1',2'-dihydroxyvinylbital, could be identified in the urine of rats treated with vinylbital or its epoxide. 2. Attempts to synthesize 1',2'-dihydroxyvinylbital from 1',2'-epoxyvinylbital by acidic hydrolysis revealed that this possible metabolite decomposes readily to 5-(1'-methylbutyl)barbituric acid by a 'retro-aldol type' reaction. 3. In rat liver microsomal preparation 1',2'-epoxyvinylbital is readily hydrated by epoxide hydratase, but this reaction is almost completely inhibited by 0.8 mM 1,1,1-trichloropropene-2,3-oxide (TCPO). This finding and the identification of 5-(1'-methylbutyl)barbituric acid as end-product of this enzyme reaction provides further evidence for the existence of an epoxide-diol pathway in the metabolism of vinylbital. 4. Vinylbital and its devinylated metabolite are excreted in 36 h urine of rats treated with vinylbital, to an extent of 0.6 +/- 1.7% of the dose (n = 5), respectively. Upon administration of 1',2-epoxyvinylbital, 59.8 +/- 14.2% of the dose (n = 5) was excreted as 5-(1'-methylbutyl)barbituric acid. 5. In 60 h urine of three human volunteers who had taken 150 mg of vinylbital orally, 2.6 +/- 1.7% of the dose was excreted as vinylbitaland 11.0 +/- 4.1% as 5-(1'-methylbutyl) barbituric acid, illustrating that also in humans the epoxide-diol pathway plays a role in the metabolism of vinylbital.