Isobolographic analysis of the antinociceptive interactions between ketoprofen and paracetamol

The present study was undertaken to evaluate the antinociceptive interaction between paracetamol and ketoprofen. The antinociceptive effect of oral administration of the drugs alone or in combination was evaluated using the mouse abdominal constriction test. The data were interpreted by isobolographic analysis to establish the nature of the interaction. The effective dose that produced 50% antinociception (ED50,mix) was calculated from the log dose-response curve of fixed-ratio combinations of paracetamol with ketoprofen. This ED50,mix was compared to the theoretical additive ED50,add by isobolographic analysis. The experimental ED50,mix was found to be significantly smaller than the theoretically calculated ED50,add, indicating a synergistic antinociceptive interaction between ketoprofen and paracetamol. Pharmacokinetic studies were carried out with mice treated with combined ketoprofen (12 mg/kg) and paracetamol (36 mg/kg). Plasma levels of ketoprofen were not changed by concurrent paracetamol treatment, and similarly no statistically significant difference was observed between paracetamol alone and the combination with ketoprofen. The pharmacokinetic analysis revealed that the combination of ketoprofen with paracetamol exerted a synergistic (supra-additive) interaction that was not associated with a pharmacokinetic interaction. The results of this study demonstrate significant synergism between ketoprofen and paracetamol.