重水素標識アミノピリンの代謝における同位体効果

概要

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The kinetic isotope effects in the in vivo metabolism of three kinds of deuterated aminopyrine (AM), i.e., AM-3-CD_3,AM-2-CD_3 and AM-4-N (CD_3)_2,were investigated. In order to evaluate the effect of deuterium labeling on the metabolic rate of AM, an equimolar mixture of AM and AM-3-CD_8 (AM : AM-3-CD_3), AM : AM-2-CD_3 or AM : AM-4-N (CD_3)_2,was orally administered to rats. Urinary metabolites were extracted with chloroform and the extracts were subjected to gas chromatograph-mass spectrometer after trimethylsilylation. AM metabolites were measured by using selected ion monitoring focused on their molecular ions. The kinetic isotope effect was estimated from the ratio of the amount of the metabolite excreted from deuterated AM to that excreted from AM (D/H ratio). After the administration of AM : AM-3-CD_3,D/H ratios of 3-hydroxymethyl metabolites were in the range of 0.347 to 0.403. On the contrary, D/H ratios of 4-demethylamino metabolites were in the range of 1.22 to 1.30. These values indicated that the deuterium labeling of AM shifted the initial step of AM metabolism from oxidation of the 3-methyl group to demethylation of the 4-dimethylamino group. This isotope effect is well-known as a "metabolic switching". In the case of AM-4-N (CD_3)_2,D/H ratio of 4-formylaminoantipyrine indicated the effect on the oxidative formylation by deuterium labeling.
社団法人日本薬学会の論文
1981-06-25