Metabolic N-oxygenation of 2,4-diamino-6-substituted pyrimidines

Biological oxidation of 2,4-diamino-6-substituted pyrimidines have been studied using hepatic microsomes from various mammalian species. The nature of the enzyme(s) involved in the oxidation has been elucidated using various enzyme inhibitors and inducing agents. The 3-N-oxides were formed with 6-pi...

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Bibliographic Details
Published in:European journal of drug metabolism and pharmacokinetics 1987-10, Vol.12 (4), p.253-258
Main Authors: EL-GHOMARI, K, GORROD, J. W
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Chromatography, High Pressure Liquid
Cricetinae
Enzyme Induction
Enzyme Inhibitors - pharmacology
General pharmacology
Guinea Pigs
Male
Medical sciences
Mesocricetus
Mice
Mice, Inbred Strains
Microsomes, Liver - metabolism
Oxidation-Reduction
Oxidoreductases - metabolism
Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions
Pharmacology. Drug treatments
Pyrimidines - analysis
Pyrimidines - metabolism
Rats
Rats, Inbred Strains
Triazines - metabolism
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Summary:Biological oxidation of 2,4-diamino-6-substituted pyrimidines have been studied using hepatic microsomes from various mammalian species. The nature of the enzyme(s) involved in the oxidation has been elucidated using various enzyme inhibitors and inducing agents. The 3-N-oxides were formed with 6-piperidino-, 6-diethylamino-, 6-methyl-, and 6-chloro-substituted 2,4-diaminopyrimidines: no evidence of 1-N-oxide formation was obtained. With the 6-hydroxy-, 6-amino-, and unsubstituted 2,4-diaminopyrimidines and melamine, no N-oxidative metabolite was detected. The differences in N-oxide formation was discussed in terms of the effect of substituents on tautomerism and electron distribution. The N-oxygenation was mediated via a cytochrome P450 dependent system.
ISSN:0378-7966
2107-0180
DOI:10.1007/BF03189908