PHARMACOKINETIC-PHARMACODYNAMIC MODELING OF THE ANTINOCICEPTIVE EFFECT OF DICLOFENAC IN THE RAT

The relationship between the pharmacokinetics and the antinociceptive effect of diclofenac was evaluated using the pain-induced functional i mpairment model in the rat. Male Wistar rats were injected with uric a cid in the knee joint of the right hind limb, which induced its dysfun ction. Once the dysfunction was complete, animals received a p.o. dose of 0.56, 1, 1.8, 3.2, 5.6 or 10 mg/kg of sodium diclofenac, and the a ntinociceptive effect and drug blood concentration were simultaneously evaluated at selected times for a period of 6 h. Diclofenac produced a dose-dependent antinociceptive effect, measured as a recovery of the functionality of the injured limb. However, the onset of the antinoci ceptive effect was delayed with respect to blood concentrations. Moreo ver, the effect lasted longer than expected from pharmacokinetic data. Therefore, when functionality index was plotted against diclofenac bl ood concentration, an anticlockwise hysteresis loop was observed for a ll doses. Hysteresis collapse was achieved using the effect-compartmen t model, and the plot of functionality index against diclofenac concen tration in the effect-compartment data was well fitted by the sigmoida l E-max model, Our data suggest slow equilibrium kinetics between dicl ofenac concentration in blood and at its site of action, which leads t o a delayed onset of the antinociceptive effect as well as a longer du ration of the response resulting from drug accumulation in synovial fl uid.