Pharmacokinetic/Pharmacodynamic Modeling of the Antinociceptive Effects of (+)-Tramadol in the Rat: Role of Cytochrome P450 2D Activity
- Marı́a J. Garrido,
- Onintza Sayar,
- Cristina Segura,
- Javier Rapado,
- Marı́a Carmen Dios-Viéitez,
- Marı́a Jesús Renedo and
- Iñaki F. Trocóniz
- Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona, Spain
- Dr. Iñaki F. Trocóniz, Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra; Irunlarrea s/n, Pamplona 31080, Spain. E-mail: itroconiz{at}unav.es
Abstract
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 (CLME0) was significantly lower (P < 0.05) in animals receiving Q. Inhibition of both (+)-M1 formation clearance (CLM10) and CLME0 were modeled by an inhibitoryEMAX model, and the estimates (relative standard error) of the maximum degree of inhibition (EMAX) and IC50, plasma concentration of Q eliciting half of EMAXfor CLM10 and CLME0, 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.
Footnotes
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This work was supported by Grünenthal GmbH (Aachen, Germany).
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DOI: 10.1124/jpet.102.047779
- Abbreviations:
- (+)-
- (−)-M1, (+)-, (−)-O-demethyltramadol
- (+)-
- (−)-T, (+)-, (−)-tramadol
- Ce
- concentration in the effect site
- CLD
- distribution clearance
- CLM10
- initial (+)-M1 formation clearance
- CLM2
- clearance representing other routes of (+)-T elimination
- CLME0
- initial apparent (+)-M1 elimination clearance
- CYP2D
- D1, D6, cytochromes P450 2D, 2D1, and 2D6
- E0
- baseline latency
- HPLC
- high-performance liquid chromatography
- ke0
- first-order rate constant governing drug distribution from plasma to the effect site
- pk/pd
- pharmacokinetic/pharmacodynamic
- Q
- quinine
- RSE
- relative standard error
- V
- apparent volume of distribution of the central compartment
- VT
- apparent volume of distribution outside the central compartment
- Z
- shape of the Weibull probability distribution
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- Received December 5, 2002.
- Accepted January 31, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
