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

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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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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).

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