Summary
The metabolism of tramadol was investigated in vitro using microsomal fractions of human liver. The parent compound and its main metabolites were determined by a newly developed high performance liquid chromatography assay. O-demethylation of tramadol was found to be stereoselective. The Vmax of the O-demethylation of (−)-tramadol was 210 pmol·mg−·min−1, whereas (+)-tramadol was O-demethylated with a Vmax of 125 pmol·mg−1·min−1. The Km for both enantiomers was determined to be 210 μM. O-demethylation was inhibited competitively by quinidine (ki=15 nM) and propafenone (ki=34 nM). N-demethylation was also stereoselective, preferentially metabolizing the (+)-enantiomer. Whereas O-demethylation displayed monophasic Michaelis-Menten kinetics, N-demethylation was best described by a two-site model. Competitive inhibition of the O-demethylation both by quinidine and propafenone suggests that O-demethylation is carried out by P-450IID6.
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Abbreviations
- HPLC:
-
high performance liquid chromatography
- ki :
-
inhibitory constant
- km :
-
apparent Michaelis-Menten constant
- M1:
-
O-demethylated metabolite of tramadol
- M2:
-
N-demethylated metabolite of tramadol
- NADP:
-
nicotinamide-adenine dinucleotide phosphate
- T:
-
tramadol
- vmax :
-
maximum velocity of the reaction
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Paar, W.D., Frankus, P. & Dengler, H.J. The metabolism of tramadol by human liver microsomes. Clin Investig 70, 708–710 (1992). https://doi.org/10.1007/BF00180294
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DOI: https://doi.org/10.1007/BF00180294