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

• 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
• ISSN: 0378-7966; 2107-0180
• DOI: 10.1007/BF03189908

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.