The metabolism of tramadol by human liver microsomes.

Dengler HJ.

Zentrum fur Innere Medizin-Allgemeine Innere Medizin, Universitat Bonn.

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.

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Interaction of the central analgesic, tramadol, with the uptake and release of 5-hydroxytryptamine in the rat brain in vitro.

Reimann W.

Grunenthal GmbH, Abteilung Pharmakologie, Aachen, Germany.

1. Tramadol is a centrally acting analgesic with low opioid receptor affinity and therefore presumably other mechanisms of analgesic action. Tramadol inhibits noradrenaline uptake but since 5-hydroxytryptamine (5-HT) is also involved in the modulation of pain perception, we tested the effects of tramadol on 5-HT uptake and release in vitro. 2. Tramadol inhibited the uptake of [3H]-5-HT into purified rat frontal cortex synaptosomes with an IC50 of 3.1 microM. The (+)-enantiomer was about four times more potent than the (-)-enantiomer; the main metabolite of tramadol, O-desmethyltramadol, was about ten times less potent. 3. Rat frontal cortex slices were preincubated with [3H]-5-HT, then superfused and stimulated electrically. Tramadol facilitated the basal outflow of [3H]-5-HT, at concentrations greater than 1 microM, while the uptake inhibitor 5-nitroquipazine enhanced both basal and stimulation-evoked overflow. Effects of the (+)-enantiomer were more potent than either the racemate, the (-)-enantiomer or the principal metabolite. 4. The effects of tramadol on the basal outflow of [3H]-5-HT were almost completely abolished when the superfusion medium contained a high concentration of the selective 5-HT uptake blocker, 6-nitroquipazine. 5. The results provide evidence for an interaction of tramadol with the neuronal 5-HT transporter. An intact uptake system is necessary for the enhancement of extraneuronal 5-HT concentrations by tramadol indicating an intraneuronal site of action.

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Effects of the analgesic agent tramadol in normal and arthritic rats: comparison with the effects of different opioids, including tolerance and cross-tolerance to morphine.

Guilbaud G.

Unite de Recherche de Physiopharmacologie du Systeme Nerveux, I.N.S.E.R.M., U 161, Paris, France.

The effects of the analgesic agent tramadol (0.1-1 mg/kg i.v.) were compared to those of the mixed agonist-antagonist analgesics nalbuphine (1 mg/kg i.v.) and buprenorphine (3 micrograms/kg i.v.) in the vocalization threshold to paw pressure test. Normal and Freund's adjuvant-induced arthritic rats were used. We have shown previously that these animals used as a model of clinical pain exhibit an enhanced sensitivity to morphine (0.1-1 mg/kg i.v.), with a rapid development of tolerance after repetitive low doses, a response not observed in normal rats. In the present study, the antinociceptive effects of tramadol, buprenorphine and nalbuphine were enhanced (by 2- to 5-fold) in arthritic compared to normal rats. In this model, these effects were significantly reduced by a dose of naloxone (0.1 mg/kg i.v.) that completely antagonized the effect of morphine. In this model, the antinociceptive effect of tramadol (1 mg/kg i.v.) was comparable to that of nalbuphine (1 mg/kg i.v.), buprenorphine (3 micrograms/kg i.v.) and morphine (1 mg/kg i.v.). Repeated administration of low doses of tramadol twice daily for 4 days to arthritic rats did not induce tolerance, in contrast to nalbuphine, buprenorphine, and morphine. In addition, no cross-tolerance between tramadol and morphine was observed in these animals.

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Postoperative patient-controlled analgesia with tramadol: analgesic efficacy and minimum effective concentrations.

Horrichs-Haermeyer G.

Department of Anaesthesiology, University of Cologne, FRG.

Forty patients (ASA status I-III) recovering from major orthopedic or gynecological operations were investigated to evaluate analgesic efficacy and threshold concentrations of tramadol and its main metabolite O-demethyltramadol (M1) in serum during the early postoperative period, using patient-controlled analgesia (PCA) by means of the Abbott Lifecare Infuser. Following an individualized intravenous loading dose of 97.5 +/- 42.3 mg (mean, SD), tramadol demand doses were 20 mg with a limit of 500 mg within 4 h; the lockout time was set to 5 min. The duration of PCA was 20.5 +/- 4.8 h. During this time 8.0 +/- 5.0 demands per patient were recorded, resulting in an average tramadol consumption of 257.5 +/- 102.8 mg (including loading dose). Analgesia was mostly judged good to excellent. Side effects were only of minor intensity and never gave rise to concern. There were no statistically significant differences between the types of surgery. Tramadol proved to be about 1/6 to 1/10 as potent an analgesic as morphine when both intensity and duration of effect were considered. Minimum effective tramadol serum concentration (MEC) varied greatly and could be best described by a log-normal distribution (range 20.2-986.3 ng/ml, median 287.7 ng/ml). Intraindividual MEC variability was lower than intersubject variability (38.2 vs 59.1%). Median M1 concentrations were 36.2 ng/ml.

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