In vitro and in vivo characterization of tapentadol metabolites.
In vitro and in vivo characterization of tapentadol metabolites.
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DOI：
10.1358/mf.2010.32.1.1434165
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发表时间：
2010
影响因子：
--
通讯作者：
R. Terlinden;B. Y. Kögel;W. Englberger;T. Tzschentke
中科院分区：
文献类型：
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作者：
R. Terlinden;B. Y. Kögel;W. Englberger;T. Tzschentke
他喷他多是一种新型的中枢作用镇痛药，在单个分子中结合了微阿片受体（莫尔）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形成有助于镇痛和/或副作用的活性代谢物，并且所涉及的细胞色素P450酶复合物可引起药代动力学药物-药物相互作用和由于酶多态性引起的药物疗效的变异性。在这里，我们报告他喷他多代谢物的相关性。在小鼠甩尾试验中，9种代谢产物（包括主要代谢产物他喷他多-O-葡糖苷酸）无镇痛作用。在小鼠苯醌扭体实验中，只有5个代谢产物显示出镇痛作用。镇痛的存在或不存在与中度活动（0.5 μ M 45）。因此，他喷他多不太可能形成在任何相关程度上有助于其镇痛活性的代谢物。
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 45). Thus, it is highly unlikely that tapentadol forms metabolites that contribute in any relevant degree to its analgesic activity.