Pharmacokinetic-pharmacodynamic modeling of the antinociceptive effects ofmain active metabolites of tramadol, (+)-O-desmethyltramadol and (2)-O-desmethyltramadol, in rats

The pharmacokinetics and pharmacodynamics of the two main metabolites of tr amadol, (+)-O-desmethyltramadol and (-)-O-desmethyltramadol, were studied i n rats. Pharmacodynamic endpoints evaluated were respiratory depression, me asured as the change in arterial blood pCO(2), pO(2), and pH levels; and an tinociception, measured by the tail-flick technique. The administration of 10 mg/kg (+)-O-desmethyltramadol in a 10-min i.v. infusion significantly al tered pCO(2), pO(2), and pH values in comparison with baseline and lower-do se groups (P < .05). However, 2 mg/kg administered in a 10-min i.v. infusio n was enough to achieve 100% antinociception without respiratory depression . Moreover, the beta-funaltrexamine pretreatment completely eliminated the antinociception of the 2-mg/kg dose, suggesting that such an effect is due to mu-opioid receptor activation. To describe and adequately characterize t he in vivo antinociceptive effect of the drug, (+)-O-desmethyltramadol was given at different infusion rates of varying lengths (10-300 min). Pharmaco kinetics was best described by a two-compartmental model. The time course o f response was described using an effect compartment associated with a line ar pharmacodynamic model. The estimates of the slope of the effect versus c oncentration relationship were significantly decreased (P < .05) as the len gth of infusion was increased, suggesting the development of tolerance. Dos es of up to 8 mg/kg (2)-O-desmethyltramadol given in 10-min i.v. infusion d id not elicit either antinociception in the tail-flick test or respiratory effects. These in vivo results are in accordance with the opiate and nonopi ate properties reported for these compounds in several in vitro studies.