在大鼠肝微粒体中反式曲马朵和反式氧去甲基曲马朵对映体代谢的性别差异

靳淑敏; 刘会臣

在大鼠肝微粒体中反式曲马朵和反式氧去甲基曲马朵对映体代谢的性别差异

Gender-related differences in metabolism of the enantiomers of trans tramadol and trans O-demethyltramadol in rat liver microsomes

摘要

摘要: 目的研究反式曲马朵(trans T)对映体代谢，反式氧去甲基曲马朵(Ml)对映体生成及其与葡糖醛酸结合的性别差异。方法以trans T或Ml为底物分别与大鼠肝微粒体孵育，高效毛细管电泳法测定孵育液中trans T和Ml对映体。结果与(+)-对映体相比，(-)-trans T优先代谢，(-)-Ml优先生成。在雌性大鼠肝微粒体中(-)-Ml优先与葡糖醛酸结合；Ml两对映体生成及其与葡糖醛酸结合的CL_int比值偏离1的程度较大。在雄性大鼠肝微粒体中(+)-Ml优先与葡糖醛酸结合。结论Trans T代谢，M1生成及其与葡糖醛酸结合均具立体选择性和性别差异；Ml生成及其与葡糖醛酸结合立体选择性的程度以雌性大鼠的较高。

Abstract: AimTo investigate the gender-related differences in the metabolism of trans tramadol (trans T) enantiomers and the glucuronidation of trans O-demethyltramadol (M1) enantiomers. Methods in vitro, trans T or M1 were separately incubated with liver microsomes of male or female rats. The concentrations of the enantiomers of trans T and M1 were determined by an HPCE method.Results Compared with (+)-enantiomers, (-)-trans T was preferentially metabolized, and (-)-M1 was produced faster in rat liver microsomes. (+)-M1 and (-)-M1 were preferentially glucuronidated in the liver microsomes of male and female rats, respectively. Compared with those in male rat liver microsomes, the enantiomeric ratios of CLint for M1 formation and M1 glucuronidation were more deviated from 1 in female rat liver microsomes. Conclusionin vitro, trans T metabolism, M1 formation and M1 glucuronidation were found to be stereoselective in rat liver microsomes. There were gender-related differences in the stereoselectivity in M1 formation and M1 glucuronidation, with a larger extent in female rat liver microsomes.

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