Enantioselective pharmacokinetics of tramadol in CYP2D6 extensive and poor metabolizers.
OBJECTIVE
To describe in detail the intravenous, single oral and multiple oral dose enantioselective pharmacokinetics of tramadol in CYP2D6 extensive metabolizers (EMs) and poor metabolizers (PMs).


METHODS
Eight EMs and eight PMs conducted three phases as an open-label cross-over trial with different formulations; 150 mg single oral tramadol hydrochloride, 50 mg single oral tramadol hydrochloride every 8 h for 48 h (steady state), 100 mg intravenous tramadol hydrochloride. Urine and plasma concentrations of (+/-)-tramadol and (+/-)-M1 were determined for 48 h after administration.


RESULTS
In all three phases, there were significant differences between EMs and PMs in AUC and t(1/2) of (+)-tramadol (P< or =0.0015), (-)-tramadol (P< or =0.0062), (+)-M1 (P< or =0.0198) and (-)-M1 (P< or =0.0370), and significant differences in C(max) of (+)-M1 (P<0.0001) and (-)-M1 (P< or =0.0010). In Phase A and C, significant differences in t(max) were seen for (+)-M1 (P< or =0.0200). There were no statistical differences between the absolute bioavailability of tramadol in EMs and PMs. The urinary recoveries of (+)-tramadol, (-)-tramadol, (+)-M1 and (-)-M1 were statistically significantly different in EMs and PMs (P<0.05). Median antimodes of the urinary metabolic ratios of (+)-tramadol / (+)-M1 and (-)-M1 were 5.0 and 1.5, respectively, hereby clearly separating EMs and PMs in all three phases.


CONCLUSIONS
The impact of CYP2D6 phenotype on tramadol pharmacokinetics was similar after single oral, multiple oral and intravenous administration displaying significant pharmacokinetic differences between EMs and PMs of (+)-tramadol, (-)-tramadol, -(+)-M1 and (-)-M1. The O-demethylation of tramadol was catalysed stereospecific by CYP2D6 in the way that very little (+)-M1 was produced in PMs.
Pedersen
Rasmus Steen
RS
Institute of Public Health, Clinical Pharmacology, University of Southern Denmark, Winslowparken 19, 5000, Odense C, Denmark. rpedersen@health.sdu.dk
Damkier
Per
P
Brøsen
Kim
K
D000328:Adult; D000701:Analgesics, Opioid / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000652:urine; D001682:Biological Availability; D018592:Cross-Over Studies; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D006801:Humans; D008297:Male; D013237:Stereoisomerism; D014147:Tramadol / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000652:urine
D000701:Analgesics, Opioid; D014147:Tramadol; D019389:Cytochrome P-450 CYP2D6