Modeling of the In Vivo Antinociceptive Interaction between an Opioid Agonist, (+)-O-Desmethyltramadol, and a Monoamine Reuptake Inhibitor, (−)-O-Desmethyltramadol, in Rats1
- 1Department of Pharmacology, Faculty of Medicine, University of the Basque Country, Bilbao (M.J.G., M.V., R.C.); 2Department of Clinical Pharmacology, University Hospital, Pamplona (M.A.C.); and 3Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Navarra, Pamplona, Spain (I.F.T.)
Abstract
The pharmacokinetic-pharmacodynamic (pk-pd) characterization of the in vivo antinociceptive interaction between (+)-O-desmethyltramadol [(+)-M1] and (−)-O-desmethyltramadol [(−)-M1], main metabolites of tramadol, was studied in three groups of rats. (+)-M1 and (−)-M1, both with different pd properties, were studied under steady-state and nonsteady-state conditions, depending on the group. Plasma drug concentration and antinociception were simultaneously measured in each animal by using an enantioselective analytical assay and the tail-flick test, respectively. Respiratory depression also was evaluated in another series of experiments according to the same experimental conditions. The pk behavior was similar for both enantiomers and no significant (P > .05) interaction between two compounds was found at this level. However, a significant (P < .01) potentiation in the antinociceptive effect elicited by (+)-M1 was found during and after (−)-M1 administration. The pd model used to describe the time course of the antinociception in the presence of (+)-M1, (−)-M1, or both is based on previous knowledge of the compounds and includes the following: 1) an effect compartment model to account for the opioid effect of (+)-M1, and 2) an indirect response model accounting for the release of noradrenaline (NA) caused by (+)-M1, and the inhibition of the NA reuptake due to the action of (−)-M1. The model predicts a positive contribution to antinociception of the predicted increasing levels of NA. No significant (P > .05) respiratory effects were seen during or after (+)-M1 and (−)-M1 administration.
Footnotes
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Send reprint requests to: Dr. María J. Garrido, Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Navarra, Apartado 177, Pamplona 31080, Spain. E-mail: mgarrido{at}unav.es
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↵1 This work was supported by a postdoctoral grant (to M.J.G.) from the Government of Basque Country, Spain.
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↵2 Current address: Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Navarra, Pamplona 31080, Spain.
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↵3 Current address: Department of Biopharmaceutical Sciences, School of Pharmacy, University of California, San Francisco, CA 94143.
- Abbreviations:
- (+)-M1
- (+)-O-desmethyltramadol
- (−)-M1
- (−)-O-desmethyltramadol
- pk-pd
- pharmacokinetic-pharmacodynamic
- NA
- noradrenaline
- Cl
- plasma clearance
- Ce
- concentrations in the biophase
- ke0
- first order rate constant governing the distribution from plasma to biophase
- KIN
- first order rate constant of release of NA
- KOUT
- first order rate constant of reuptake of NA
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- Received March 23, 2000.
- Accepted June 21, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
