Received for publication December 16, 2002.
Revised January 2, 2003.
Accepted for publication January 31, 2003.

Pharmacokinetic/Pharmacodynamic modelling of the antinociceptive effects of (+)-Tramadol in the rat: Role of the CYP2D activity

Abstract

In this study the role of the CYP2D in the pharmacokinetic/pharmacodynamic (pk/pd) relationship of (+)-Tramadol [(+)-T] has been explored in rats. Male Wistar rats were infused with (+)-T in absence and during a pre-treatment with a reversible CYP2D inhibitor quinine (Q), determining plasma concentrations of Q, (+)-T, and (+)-O-demethyltramadol [(+)-M1], and measuring antinociception. Pk of (+)-M1, but not (+)-T, was affected by Q pre-treatment: At early times 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 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 (CL_M10) and CL_ME0, was modelled by an inhibitory E_MAX model and the estimates (RSE) of maximum degree of inhibition (EMAX) and IC₅₀, plasma concentration of Q eliciting half of E_MAX for CL_M10 and CL_ME0, were 0.94 (0.04), 97 (0.51) ng/ml, and 48 (0.42) ng/ml, respectively. The modelling 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.

Key words: (+)-tramadol, CYP2D activity, Pharmacokinetic/pharmacodinamic modeling, Pharmacokinetics, antinociception, metabolism

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