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


CONCLUSIONS
(+/-)-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.
Liu
Hui-Chen
HC
Department of Clinical Pharmacology, Bethune International Peace Hospital, Shijiazhuang 050082, China. lhcl@heinfo.net
Wang
Na
N
Yu
Yang
Y
Hou
Yan-Ning
YN
D000701:Analgesics, Opioid / Q000378:metabolism*; D000818:Animals; D003915:Dextromethorphan / Q000494:pharmacology; D005473:Fluoxetine / Q000494:pharmacology; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D011405:Propafenone / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D014147:Tramadol / Q000031:analogs & derivatives* / Q000378:metabolism*
D000701:Analgesics, Opioid; D005473:Fluoxetine; C080580:O-demethyltramadol; D014147:Tramadol; D011405:Propafenone; D003915:Dextromethorphan