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Pharmacokinetic-pharmacodynamic modeling of the antinociceptive effect of baclofen in mice

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Summary

The aim of this study was the development of a pharmacokinetic-pharmacodynamic (PK/PD) model of the antinociceptive effect of baclofen in mice. We studied the dose response curve of the analgesic action of baclofen in mice by hot plate test. Baclofen produced a dose dependent antinociceptive effect with doses between 1–3 mg/kg administered intraperitoneally (i.p.) (ED50: 1.94 mg/kg of racemate) and this effect fits to a linear pharmacodynamic model. Blood and brain concentrations of (−)3H-baclofen were determined by Thin-Layer Chromatography (TLC) and counted in the scintillation-counter. The PK/PD models were analyzed with the PC-TOPFIT V.2.0 and the tests for distinguishing between models were several adjustment parameters as Akaike information criterion (AIC), Imbimbo criterion (Ip), standard desviation (SD) and the correlation coefficient (r2). Accordingly with these adjustment parameters, a 2 compartment open model was selected where plasma is the central compartment and brain is in the peripheral compartment. In this model, the effect is linked to the peripheral compartment.

When the antinociceptive effect of baclofen was plotted against blood concentration, the resulting curve exhibed an anticlockwise hysteresis loop, but on the other hand, when the antinociceptive effect was plotted against the brain concentration, the hysteresis was collapsed. These results confirmed the selected model in our study, as the best adjustment was shown when the pharmacological response was linked to the peripheral compartment.

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References

  1. 1.

    DeFeudis F.V. (1977): GABA receptors in the vertebrate nervous system. Prog. Neurobiol., 9, 123–145.

  2. 2.

    Hösli L., Hösli E. (1978): Action and uptake of neurotransmitters in CNS tissue culture. Rev. Physiol. Biochem. Pharmac., 81, 135–188.

  3. 3.

    Johnston G.A.R. (1978): Neuropharmacology of aminoacid inhibitory transmitters. Ann. Rev. Pharmacol. Toxicol., 18, 269–289.

  4. 4.

    DeFeudis F.V. (1982): GABA-ergic analgesia-a naloxone insensitive system. Pharmac. Res. Commun., 14, 383–390.

  5. 5.

    Sawynok J. (1984): GABA-ergic mechanisms in antinociception. Prog. Neuropsychopharmac. Biol. Psychiat., 8, 581–586.

  6. 6.

    Sivam S.P., Ho I.K. (1985): Minireview, GABA in morphine analgesia and tolerance. Life Sci., 37, 199–208.

  7. 7.

    Bowery N.G., Hill D.R., Hudson A.L., Doble A., Middlemiss D.N., Shaw J., Turnbull M.J. (1980): (−)-Baclofen decreases neurotransmitter release in the mammalian CNS by an action at a novel GABA receptor. Nature, 283, 92–94.

  8. 8.

    Metha A.K., Ticku M.K. (1987): Baclofen induces catatonia in rats. Neuropharmacology, 26, 1419–1423.

  9. 9.

    Gray J.A., Goodwin G.M., Heal D.J., Green A.R. (1987): Hypothermia induced by baclofen, a possible index of GABAB receptor function in mice, is enhaced by antidepressant drugs and ECS. Brit. J. Pharmacol., 92, 863–870.

  10. 10.

    Aley K.O., Kulkarni S.K. (1990): Effect of baclofen, a GABAB agonist on forced swimming-induced immobility in mice. Arch. Int. Pharmacodyn., 307, 18–31.

  11. 11.

    Sawynok J. (1987): GABAergic mechanism of analgesia: An update. Pharmacol. Biochem. Behav., 26, 463–474.

  12. 12.

    Pedersen E., Arlien-Soborg P., Mai J. (1974): The mode of action of the GABA derivate baclofen in human spasticity. Acta Neurol. Scand., 50, 665–680.

  13. 13.

    Pinto O., DE S., Polikar M., Debono G. (1972): Results of international clinical trials with Lioresal. Postgrad. Med. J., 48 (5), 18–23.

  14. 14.

    Corly O., Roma G., Bacchini M., Battagliarini G., De Lorenzi P.P. (1984): Il baclofen come analgesico negli interventi di dilatazione, aspirazioni e curretage uterino. Min. Anest., 50, 401–405.

  15. 15.

    Balerio G.N. (1996): Efecto analgésico del baclofen: mediación del sistema GABAérgico. Doctoral Thesis. Facultad de Farmacia y Bioquimica. Universidad de Buenos Aires.

  16. 16.

    Holford N.H.G., Sheiner L.B. (1981): Understanding the dose effect relationship: Clinical application of pharmacokinetic-pharmacodynamic models. Clin. Pharmacokinet., 6, 429–453.

  17. 17.

    Dahlström B.E., Paalzow L.K., Segre G., Agren A.J. (1978): Relation between morphine pharmacokinetics and analgesia. J. Pharmacokinet. Biopharm., 6, 41–53.

  18. 18.

    Bhargava H.N., Villar V.M., Gulati A., Chari G. (1991): Analgesic and hypothermic effects of intravenously administered morphine in the rat are related to its serum levels. J. Pharmacol. Exp. Ther., 258, 511–516.

  19. 19.

    Walker J.S., Kasmerski L. (1988): Diflunisal pharmacodynamics in the experimental arthritis in rats. J. Rheumatol., 15, 1643–1647.

  20. 20.

    Shibasaki J., Konishi R., Kitasaki T., Koizumi T. (1979): Relationship between blood levels and analgesic effects of acetaminophen in mice. Chem. Pharm. Bull., 27, 129–138.

  21. 21.

    Granados-Soto V., Flores-Murrieta F.J., López-Muñoz F.J., Salazar L.A., Villarreal J.E., Castañeda-Hernández G. (1992): Relationship between paracetamol plasma levels and its analgesic effect in the rat. J. Pharm. Pharmacol., 44, 741–744.

  22. 22.

    Granados-Soto V., López-Muñoz F.J., Castañeda-Hernández G., Salazar L.A., Villarreal J.E., Flores-Murrieta F.J. (1993): Characterization of the analgesic effects of paracetamol and caffeine combinations in the pain-induced functional impairment model in the rat. J. Pharm. Pharmacol., 45, 627–631.

  23. 23.

    Eddy N.B., Leimbach D. (1953): Synthetic Analgesics. Dithienylbutenyl and Dithienylbutylamines. J. Pharmacol. Exp. Ther., 107, 385–393.

  24. 24.

    Harris L.S., Pierson A.K. (1964): Some narcotic antagonists in the benzomorphan series. J. Pharmacol. Exp. Ther., 143, 141–148.

  25. 25.

    Stahl E. (1969): Thin-Layer Chromatography. Springer-Verlag, Berlin, Heidelberg New York.

  26. 26.

    Heinzel G., Woloszczak R., Thomann P. (1993): Pharmacokinetic and Pharmacodynamic Data Analysis System for the PC. In: Heinzel G. and Tanswell P. Compartmental Analysis Methods Manual. Gustav Fisher-Stuttgart-Jena-New York. Part 3, 6–138.

  27. 27.

    Yamaoka K., Nakagawa T., Uno T. (1978): Application of Akaike_s Information Criterion (AIC) in the Evaluation of Linear Pharmacokinetic Equations. J. Pharmacokin. Biopharm., 6(2), 165–175.

  28. 28.

    Imbimbo B.P., Imbimbo E., Daniotti S., Verotta D., Bassotti G. (1988): A new criterion for selection of pharmacokinetic multi-exponential equations. J. Pharm. Sci., 9, 784.

  29. 29.

    Imbimbo B.P., Martinelli P., Rocchetti M., Ferrari G., Bassotti G., Imbimbo E. (1991): Efficiency of different criteria for selecting pharmacokinetic multiexponential equations. Biopharmaceutics & Drug Disposition, 12, 139–147.

  30. 30.

    D’Arienzo M., Pennisi M., Zanolo G., Borsa M. (1984): Ketoprofen lysine: Ketoprofen serum levels and analgesic activity. Drugs Exp. Clin. Res., 10, 863–866.

  31. 31.

    Kohler G., Primbs P., Morand J., Rubelt C. (1985): Correlation between ketoprofen plasma levels and analgesic effect in acute lumbar pain and radicular pain. Clin. Rheumatol., 4, 399–404.

  32. 32.

    Laska E.M., Sunshine A., Marrero I., Olson N., Siegel C., McCormick N. (1986): The correlation between blood levels of ibuprofen and clinical analgesic response. Clin. Pharmacol. Ther., 40, 1–7.

  33. 33.

    Inturrisi C.E., Portenoy R.K., Max M.B., Colburn W.A., Foley K.M. (1990): Pharmacokinetic-pharmacodynamic relationships of methadone infusions in patients with cancer pain. Clin. Pharmacol. Ther., 47, 565–577.

  34. 34.

    Mandema J.W., Heijligers-Feijen C.D., Tukker E., De Boer A.G., Danhof M. (1991): Modeling of the effect site equilibration kinetics and pharmacodynamics of racemic baclofen and its enantiomers using quantitative EEG effect measures. J. Pharmacol. Exp. Ther., 261(1), 88–95.

  35. 35.

    Lammers M.W., Hekster Y.A., Keyser A., van Lier H., Meinardi H., Renier W.O. (1995): Neither dosage nor serum levels of antiepileptic drugs are predictive for efficacy and adverse effects. Pharm. World Sci., 17, 201–206.

  36. 36.

    Sveinbjornsdottir S., Sander J.W., Upton D., Thomson L.P., Patsalos P.N., Hirt D., Emre M., Lowe D., Duncan J.S. (1993): The excitatory amino acid antagonist D-CPP-ene (SDZ EAA-494) in patients with epilepsy. Epilepsy Res., 16, 165–174.

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Correspondence to Graciela N. Balerio.

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Balerio, G.N., Rubio, M.C. Pharmacokinetic-pharmacodynamic modeling of the antinociceptive effect of baclofen in mice. Eur. J. Drug Metab. Pharmacokinet. 27, 163–169 (2002). https://doi.org/10.1007/BF03190452

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Keywords

  • Pharmacokinetic
  • Pharmacodynamic modeling
  • baclofen
  • antinociceptive effect
  • mice