Abstract
The pharmacokinetics and pharmacodynamics of the two main metabolites of tramadol, (+)-O-desmethyltramadol and (−)-O-desmethyltramadol, were studied in rats. Pharmacodynamic endpoints evaluated were respiratory depression, measured as the change in arterial blood pCO2, pO2, and pH levels; and antinociception, measured by the tail-flick technique. The administration of 10 mg/kg (+)-O-desmethyltramadol in a 10-min i.v. infusion significantly altered pCO2, pO2, and pH values in comparison with baseline and lower-dose groups (P < .05). However, 2 mg/kg administered in a 10-min i.v. infusion was enough to achieve 100% antinociception without respiratory depression. Moreover, the β-funaltrexamine pretreatment completely eliminated the antinociception of the 2-mg/kg dose, suggesting that such an effect is due to μ-opioid receptor activation. To describe and adequately characterize the in vivo antinociceptive effect of the drug, (+)-O-desmethyltramadol was given at different infusion rates of varying lengths (10–300 min). Pharmacokinetics was best described by a two-compartmental model. The time course of response was described using an effect compartment associated with a linear pharmacodynamic model. The estimates of the slope of the effect versus concentration relationship were significantly decreased (P < .05) as the length of infusion was increased, suggesting the development of tolerance. Doses of up to 8 mg/kg (−)-O-desmethyltramadol given in 10-min i.v. infusion did not elicit either antinociception in the tail-flick test or respiratory effects. These in vivo results are in accordance with the opiate and nonopiate properties reported for these compounds in several in vitro studies.
Footnotes
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Send reprint requests to: Iñaki F. Trocóniz PhD, Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Navarra, Pamplona 31080, Spain. E-mail:itroconiz{at}unav.es.
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↵1 This work was supported by a grant from the University of Basque Country (026, EB 231/96). M.V. was supported by a fellowship from the University of Basque Country.
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↵2 Current address: Department of Biopharmaceutical Sciences, School of Pharmacy, University of California, San Francisco, CA.
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↵3 Current address: Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Navarra, Pamplona, Spain.
- Abbreviations:
- %MPE
- percentage of maximum possible effect
- M1
- O-desmethyltramadol
- β-FNA
- β-funaltrexamine
- pk
- pharmacokinetic
- pd
- pharmacodynamic
- NA
- noradrenaline
- Cl
- total plasma clearance
- c.v.
- coefficients of variation
- Received August 31, 1999.
- Accepted January 31, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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