Paar W D, Frankus P, Dengler H J
Zentrum für Innere Medizin-Allgemeine Innere Medizin, Universität Bonn.
Clin Investig. 1992 Aug;70(8):708-10. doi: 10.1007/BF00180294.
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.
利用人肝脏微粒体组分在体外研究了曲马多的代谢情况。通过新开发的高效液相色谱分析法测定了母体化合物及其主要代谢产物。发现曲马多的O-去甲基化具有立体选择性。(-)-曲马多O-去甲基化的Vmax为210 pmol·mg-1·min-1，而(+)-曲马多O-去甲基化的Vmax为125 pmol·mg-1·min-1。两种对映体的Km均测定为210 μM。奎尼丁（ki = 15 nM）和普罗帕酮（ki = 34 nM）竞争性抑制O-去甲基化。N-去甲基化也具有立体选择性，优先代谢(+)-对映体。O-去甲基化呈现单相米氏动力学，而N-去甲基化最好用双位点模型描述。奎尼丁和普罗帕酮对O-去甲基化的竞争性抑制表明O-去甲基化是由P-450IID6进行的。
