title: The epoxide-diol pathway in the metabolism of vinylbital in rat and man.
abstract: 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.
mesh_terms: D000818:Animals; D001463:Barbiturates / Q000031:analogs & derivatives / Q000378:metabolism* / Q000652:urine; D002849:Chromatography, Gas; D004851:Epoxide Hydrolases / Q000378:metabolism; D004852:Epoxy Compounds / Q000378:metabolism; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D051381:Rats; D014753:Vinyl Compounds / Q000378:metabolism / Q000652:urine
chemical_list: D001463:Barbiturates; D004852:Epoxy Compounds; D014753:Vinyl Compounds; C013334:butylvinal; C028518:1',2'-epoxyvinylbital; D004851:Epoxide Hydrolases