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Pharmacokinetic/pharmacodynamic modeling of the antinociceptive effects of (+)-tramadol in the rat: role of cytochrome P450 2D activity
Authors: Garrido, M.J. (María Jesús)
Sayar, O. (Onintza)
Segura, C. (Cristina)
Rapado, J. (Javier)
Dios-Vieitez, M.C. (M. Carmen)
Renedo, M.J. (María Jesús)
Troconiz, I.F. (Iñaki F.)
Keywords: Antinociceptive properties
Issue Date: 2003
Publisher: American Society for Pharmacology and Experimental Therapeutics
Publisher version:
ISSN: 0022-3565
Citation: Garrido MJ, Sayar O, Segura C, Rapado J, Dios-Vieitez MC, Renedo MJ, et al. Pharmacokinetic/pharmacodynamic modeling of the antinociceptive effects of (+)-tramadol in the rat: role of cytochrome P450 2D activity. J Pharmacol Exp Ther 2003 May;305(2):710-718.
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 (CL(M10)) 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 IC(50), 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 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.
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