重水素標識Paeonolの代謝における同位体効果

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The kinetic isotope effects in the metabolism of paeonol (2-hydroxy-4-methoxy-acetophenone ; I) labeled with stable isotopes, 2-hydroxy-4-methoxy [d_3] acetophenone (I-d_3) and 2-hydroxy-4-methoxy [d_3] acetophenone [acetyl-^<13>C_2] (I-^<13>C_2d_3), were investigated. In order to evaluate the effect of deuterium labeling on the metabolic rate of I, an equimolar mixture of I and I-^<13>C_2d_3 (I : I-^<13>C_2d_3), or I and I-d_3 (I : I-d_3) was orally administered to man, rabbits, guinea pigs, rats and mice. Urinary metabolites were purified by extraction with ether and by thin-layer chromatography, then subjected to gas chromatograph-mass spectrometer after acetylation. The I-metabolites were measured by using selected ion monitoring focused on their [M-COCH_2]^+ or [M-2COCH_2]^+ ions. The kinetic isotope effect was estimated from the ratio of the amount of the metabolite excreted from stable-isotopically labeled I to that excreted from I (L/UL ratio). After the administration of I : I-^<13>C_2d_3,L/UL ratios of unchanged metabolites were in the range of 0.97 to 1.06. That is, no difference of the excretion rate between the labeled and unlabeled compounds was observed. On the contrary, L/UL ratios of 4-demethyl metabolites were in the range of 0.20 to 0.38. These values indicate that the amount of labeled metabolite is less than that of unlabeled one. Though a remarkable isotope effect was also observed in the case of 5-hydroxy metabolites, the amount of unlabeled metabolite was less than that of labeled one. After the administration of I : I-d_3 to man and rats, the same isotope effect as in the case of I : I-^<13>C_2d_3 was observed. It is suggested from these facts that the kinetic isotope effect observed in the metabolism of I : I-^<13>C_2d_3 is "Metabolic switching"due to deuteromethoxy group of I-^<13>C_2d_3.
公益社団法人日本薬学会の論文
1982-05-25

重水素標識Paeonolの代謝における同位体効果

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