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Xenobiotica
the fate of foreign compounds in biological systems
Volume 11, 1981 - Issue 8
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Research Article

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

, , , , &
Pages 547-557 | Received 10 Mar 1981, Published online: 22 Sep 2008
 

Abstract

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/pm 1±5 min (mean/pm S.D.; n = 3). A total body clearance of 35±2/pm 9±6 ml/min (mean/pm 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 1mM 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.

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