Terlinden R, Kogel B Y, Englberger W, Tzschentke T M
Department of Pharmacokinetics, Global Preclinical Research and Development, Grunenthal GmbH, Aachen, Germany.
Methods Find Exp Clin Pharmacol. 2010 Jan-Feb;32(1):31-8. doi: 10.1358/mf.2010.32.1.1434165.
Tapentadol is a novel, centrally acting analgesic combining micro-opioid receptor (MOR) agonism and noradrenaline (NA) reuptake inhibition in a single molecule. Many classic opioids form active metabolites that contribute to analgesia and/or side effects, and the involved cytochrome P450 enzyme complex can give rise to pharmacokinetic drug-drug interactions and variability in drug efficacy due to enzyme polymorphisms. Here we report on the relevance of tapentadol metabolites. Nine metabolites, including the major metabolite tapentadol-O-glucuronide, had no analgesic effects in the tail-flick test in mice. In the phenylquinone writhing test in mice, only 5 of these metabolites showed analgesic effects. The absence or presence of analgesia correlated with moderate activity (0.5 microM < K(i) < 1.1 microM) at the NA transporter or MOR. However, the systemic exposure for these metabolites found in humans after therapeutic oral doses of tapentadol was far below their respective K(i) values at these binding sites (by a factor of > 45). Thus, it is highly unlikely that tapentadol forms metabolites that contribute in any relevant degree to its analgesic activity.
曲马多是一种新型的中枢性镇痛药，它在单个分子中结合了微阿片受体（MOR）激动作用和去甲肾上腺素（NA）再摄取抑制作用。许多经典阿片类药物会形成活性代谢产物，这些代谢产物会导致镇痛和/或产生副作用，并且所涉及的细胞色素P450酶复合物可能会由于酶多态性而引发药代动力学药物-药物相互作用以及药物疗效的变异性。在此，我们报告曲马多代谢产物的相关性。九种代谢产物，包括主要代谢产物曲马多-O-葡萄糖醛酸苷，在小鼠甩尾试验中没有镇痛作用。在小鼠苯醌扭体试验中，这些代谢产物中只有5种显示出镇痛作用。镇痛作用的有无与在NA转运体或MOR上的中度活性（0.5微摩尔＜抑制常数（Ki）＜1.1微摩尔）相关。然而，在治疗剂量的曲马多口服给药后，人体中发现的这些代谢产物的全身暴露量远低于它们在这些结合位点各自的Ki值（相差＞45倍）。因此，曲马多形成的代谢产物极不可能在任何相关程度上对其镇痛活性有贡献。
