In vitro and in vivo characterization of tapentadol metabolites
| Autor: | B.Y. Kögel, Rolf Terlinden, Thomas M. Tzschentke, W. Englberger |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Male
Metabolite Analgesic Receptors Opioid mu Pain Pharmacology In Vitro Techniques chemistry.chemical_compound Mice Pharmacokinetics Phenols In vivo medicine Animals Humans Pharmacology (medical) Rats Wistar Active metabolite Adrenergic Uptake Inhibitors Dose-Response Relationship Drug Chemistry Tapentadol Rats Analgesics Opioid Disease Models Animal Opioid Female Reuptake inhibitor medicine.drug |
| Zdroj: | Methods and findings in experimental and clinical pharmacology. 32(1) |
| ISSN: | 0379-0355 |
| Popis: | 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 microMK(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 of45). Thus, it is highly unlikely that tapentadol forms metabolites that contribute in any relevant degree to its analgesic activity. |
| Databáze: | OpenAIRE |
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