Pharmacokinetic/Pharmacodynamic Modeling of the Antinociceptive Effects of (+)-Tramadol in the Rat: Role of Cytochrome P450 2D Activity

• Published in: The Journal of pharmacology and experimental therapeutics 2003-05, Vol.305 (2), p.710-718
• Main Authors: Garrido, Maria J, Sayar, Onintza, Segura, Cristina, Rapado, Javier, Dios-Vieitez, Maria Carmen, Renedo, Maria Jesus, Troconiz, Inaki F
• Format: Article
• Language: English
• Subjects: Algorithms; Analgesics, Opioid - pharmacokinetics; Analgesics, Opioid - pharmacology; Animals; Biotransformation; Chromatography, High Pressure Liquid; Cytochrome P-450 CYP2D6 - metabolism; Cytochrome P-450 CYP2D6 Inhibitors; Enzyme Inhibitors - pharmacology; Infusions, Intravenous; Male; Models, Biological; Quinine - pharmacology; Rats; Rats, Wistar; Tramadol - analogs & derivatives; Tramadol - pharmacokinetics; Tramadol - pharmacology
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.102.047779

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.