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Enantioselective pharmacokinetics of tramadol in CYP2D6 extensive and poor metabolizers

  • Pharmacokinetics and Disposition
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European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

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 t1/2 of (+)-tramadol (P≤0.0015), (−)-tramadol (P≤0.0062), (+)-M1 (P≤0.0198) and (−)-M1 (P≤0.0370), and significant differences in Cmax of (+)-M1 (P<0.0001) and (−)-M1 (P≤0.0010). In Phase A and C, significant differences in tmax were seen for (+)-M1 (P≤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.

Conclusion

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.

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Acknowledgements

We gratefully thank The Alfred Benzon Foundation, The Lundbeck Foundation, The Danish Medical Research Council and The Danish Clinical Intervention Research Academy for financial support.

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Authors and Affiliations

  1. Institute of Public Health, Clinical Pharmacology, University of Southern Denmark, Winslowparken 19, 5000, Odense C, Denmark

    Rasmus Steen Pedersen & Kim Brøsen

  2. Department of Biochemistry, Pharmacology and Genetics, Odense University Hospital, Sdr. Boulevard 29, 5000, Odense C, Denmark

    Per Damkier

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  1. Rasmus Steen Pedersen
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Correspondence to Rasmus Steen Pedersen.

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Pedersen, R., Damkier, P. & Brøsen, K. Enantioselective pharmacokinetics of tramadol in CYP2D6 extensive and poor metabolizers. Eur J Clin Pharmacol 62, 513–521 (2006). https://doi.org/10.1007/s00228-006-0135-x

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