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

AIM: To 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. CONCLUSION: In 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.

Gender-related differences in pharmacokinetics of enantiomers of trans-tramadol and its active metabolite, trans-O-demethyltramadol, in rats.

AIM: To compare the pharmacokinetics of the enantiomers of trans-tramadol (trans-T) and its active metabolite, trans-O-demethyltramadol (M1), in male and female rats. METHODS: Following a single oral dose of 10 mg/kg trans-T hydrochloride to rats, (+)-trans-T, (-)-trans-T, (+)-M1, and (-)-M1 in plasma were determined by a high performance capillary electrophoresis method. RESULTS: The females showed higher plasma concentrations of (+)-trans-T, (-)-trans-T, and (+)-M1 than the males. The enantiomers of trans-T were absorbed and eliminated more slowly in the females than in the males. (+)-M1 was eliminated more slowly in the females than in the males. All pharmacokinetic parameters but Tmax of the two enantiomers of trans-T were significantly different in both sex rats. The (+)/(-)-enantiomeric ratios of the pharmacokinetic parameters for trans-T in the males were similar to those in the females. The values of Cmax, AUC(0-infinity) of the two enantiomers of M1 were significantly different in both sex rats. The (+)/(-)-enantiomeric ratios of Cmax, AUC(0-infinity) for M1 were lower than 1 in the males, larger than 1 in the females. CONCLUSIONS: Systemic exposure of (+)-trans-T, (-)-trans-T, and (+)-M1 was higher in female rats than in male rats. The stereoselectivity in pharmacokinetics of trans-T was similar, and that of M1 was different in male and female rats.