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-1.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 microM. 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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