TY - JOUR T1 - Pharmacokinetic-Pharmacodynamic Modeling of the Antinociceptive Effects of Main Active Metabolites of Tramadol, (+)-<em>O</em>-Desmethyltramadol and (−)-<em>O</em>-Desmethyltramadol, in Rats JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 646 LP - 653 VL - 293 IS - 2 AU - Marta Valle AU - María J. Garrido AU - Juan M. Pavón AU - Rosario Calvo AU - Iñaki F. Trocóniz Y1 - 2000/05/01 UR - http://jpet.aspetjournals.org/content/293/2/646.abstract N2 - 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 &lt; .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 &lt; .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. The American Society for Pharmacology and Experimental Therapeutics ER -