IN VITRO AND IN VIVO CHARACTERIZATION OF TAPENTADOL METABOLITES

Tapentadol is a novel, centrally acting analgesic combining mu-opioid receptor (MOP) 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 topentado-10-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 mu M < K-j < 1.1 mu M) at the NA transporter or MOP. However; the systemic exposure for these metabolites found in humans after therapeutic oral doses of topentadol was far below their respective K, 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.