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

N P Vermeulen, D D Breimer, J.J.M. Holthuis, C. van Mol, B H Bakker, A. van der Gen

Research output: Contribution to JournalArticleAcademicpeer-review

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 +/- 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.

Original languageEnglish
Pages (from-to)547-57
Number of pages11
JournalXenobiotica
Volume11
Issue number8
Publication statusPublished - Aug 1981

Fingerprint

Rats
Epoxy Compounds
Metabolites
Trichloroepoxypropane
Hexobarbital
Epoxide Hydrolases
Liver
Ionization
Mass spectrometry
Half-Life
Mass Spectrometry
Nitrogen
Urine
Electrons
Kidney
Plasmas
1',2'-epoxyhexobarbital
3'-ketohexobarbital

Keywords

  • Animals
  • Biotransformation
  • Hexobarbital
  • In Vitro Techniques
  • Liver
  • Male
  • Methylation
  • Microsomes, Liver
  • Mutagens
  • Proteins
  • Rats
  • Rats, Inbred Strains
  • Salmonella typhimurium
  • Journal Article

Cite this

Vermeulen, N. P., Breimer, D. D., Holthuis, J. J. M., van Mol, C., Bakker, B. H., & van der Gen, A. (1981). The metabolic fate of 1',2'-epoxyhexobarbital in the rat. Xenobiotica, 11(8), 547-57.
Vermeulen, N P ; Breimer, D D ; Holthuis, J.J.M. ; van Mol, C. ; Bakker, B H ; van der Gen, A. / The metabolic fate of 1',2'-epoxyhexobarbital in the rat. In: Xenobiotica. 1981 ; Vol. 11, No. 8. pp. 547-57.
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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 +/- 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.",
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Vermeulen, NP, Breimer, DD, Holthuis, JJM, van Mol, C, Bakker, BH & van der Gen, A 1981, 'The metabolic fate of 1',2'-epoxyhexobarbital in the rat' Xenobiotica, vol. 11, no. 8, pp. 547-57.

The metabolic fate of 1',2'-epoxyhexobarbital in the rat. / Vermeulen, N P; Breimer, D D; Holthuis, J.J.M.; van Mol, C.; Bakker, B H; van der Gen, A.

In: Xenobiotica, Vol. 11, No. 8, 08.1981, p. 547-57.

Research output: Contribution to JournalArticleAcademicpeer-review

TY - JOUR

T1 - The metabolic fate of 1',2'-epoxyhexobarbital in the rat

AU - Vermeulen, N P

AU - Breimer, D D

AU - Holthuis, J.J.M.

AU - van Mol, C.

AU - Bakker, B H

AU - van der Gen, A.

PY - 1981/8

Y1 - 1981/8

N2 - 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.

AB - 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.

KW - Animals

KW - Biotransformation

KW - Hexobarbital

KW - In Vitro Techniques

KW - Liver

KW - Male

KW - Methylation

KW - Microsomes, Liver

KW - Mutagens

KW - Proteins

KW - Rats

KW - Rats, Inbred Strains

KW - Salmonella typhimurium

KW - Journal Article

M3 - Article

VL - 11

SP - 547

EP - 557

JO - Xenobiotica

JF - Xenobiotica

SN - 0049-8254

IS - 8

ER -

Vermeulen NP, Breimer DD, Holthuis JJM, van Mol C, Bakker BH, van der Gen A. The metabolic fate of 1',2'-epoxyhexobarbital in the rat. Xenobiotica. 1981 Aug;11(8):547-57.