In this study the role of cytochrome P450 2D (CYP2D) in the pharmacokinetic/pharmacodynamic relationship of (+)-tramadol [(+)-T] has been explored in rats. Male Wistar rats were infused with (+)-T in the absence of and during pretreatment with a reversible CYP2D inhibitor quinine (Q), determining plasma concentrations of Q, (+)-T, and (+)-O-demethyltramadol [(+)-M1], and measuring antinociception. Pharmacokinetics of (+)-M1, but not (+)-T, was affected by Q pretreatment: early after the start of (+)-T infusion, levels of (+)-M1 were significantly lower (P < 0.05). However, at later times during Q infusion those levels increased continuously, exceeding the values found in animals that did not receive the inhibitor. These results suggest that CYP2D is involved in the formation and elimination of (+)-M1. In fact, results from another experiment where (+)-M1 was given in the presence and in absence of Q showed that (+)-M1 elimination clearance (CL_ME0) was significantly lower (P < 0.05) in animals receiving Q. Inhibition of both (+)-M1 formation clearance (CLM₁₀) and CL_ME0 were modeled by an inhibitory E_MAX model, and the estimates (relative standard error) of the maximum degree of inhibition (E_MAX) and IC₅₀, plasma concentration of Q eliciting half of E_MAX for CLM₁₀ and CL_ME0, were 0.94 (0.04), 97 (0.51) ng/ml, and 48 (0.42) ng/ml, respectively. The modeling of the time course of antinociception showed that the contribution of (+)-T was negligible and (+)-M1 was responsible for the observed effects, which depend linearly on (+)-M1 effect site concentrations. Therefore, the CYP2D activity is a major determinant of the antinociception elicited after (+)-T administration.

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 ?-funaltrexamine pretreatment completely eliminated the antinociception of the 2-mg/kg dose, suggesting that such an effect is due to ?-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.

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