Stereoselectivity in trans-tramadol metabolism and trans-O-demethyltramadol formation in rat liver microsomes

Acta Pharmacol Sin. 2003 Jan;24(1):85-90.


Aim: To study the stereoselectivity in trans-tramadol [(+/-)-trans-T] metabolism and trans-O-demethyltramadol (M1) formation.

Methods: (+)-, (-)-, Or (+/-)-trans-T was separately incubated with rat liver microsomes in vitro. The concentrations of (+/-)-trans-T and M1 enantiomers were determined by high performance capillary electrophoresis (HPCE).

Results: When each enantiomer of (+/-)-trans-T was incubated with rat liver microsomes, the metabolic rate of (+)-trans-T was lower than that of (-)-trans-T. The kinetics of (+)-, (-)-M1 formation was found to fit the single-enzyme Michaelis-Menten model. The Vmax and CLint of (+)-M1 formation were lower than those of (-)-M1 formation. When (+/-)-trans-T was used as the substrate, the metabolic rates of (+)-, (-)-trans-T, and the formation rates of (+)-M1, (-)-M1 decreased to different extents. Dextromethorphan (Dex), propafenone (Pro), and fluoxetine (Flu) could inhibit both the metabolism of (+/-)-trans-T enantiomers and the formation of M1 enantiomers. Pro and Flu were shown to enhance the stereoselectivity in both (+/-)-trans-T metabolism and M1 formation, and Dex could only enhance that in M1 formation.

Conclusion: (+/-)-Trans-T metabolism and M1 formation were stereoselective, (-)-trans-T being preferentially metabolized and (-)-M1 being preferentially formed. There was interaction in metabolism between (+/-)-trans-T enantiomers. Dex, Pro, and Flu had different effects on the stereoselectivity.

MeSH terms

  • Analgesics, Opioid / metabolism*
  • Animals
  • Dextromethorphan / pharmacology
  • Fluoxetine / pharmacology
  • Male
  • Microsomes, Liver / metabolism*
  • Propafenone / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Stereoisomerism
  • Tramadol / analogs & derivatives*
  • Tramadol / metabolism*


  • Analgesics, Opioid
  • Fluoxetine
  • O-demethyltramadol
  • Tramadol
  • Propafenone
  • Dextromethorphan