DEVELOPMENT OF A NEW QUANTITATIVE APPROACH FOR THE ISOBOLOGRAPHIC ASSESSMENT OF THE CONVULSANT INTERACTION BETWEEN PEFLOXACIN AND THEOPHYLLINE IN RATS

Purpose, A new mathematical approach was developed to quantify convuls ant interaction between pefloxacin and theophylline in rats. Methods, Animals received each compound separately or in different combination ratios. Infusion was stopped at the onset of maximal seizures. Cerebro spinal fluid (CSF) and plasma samples were collected for HPLC drug det ermination. The nature and intensity of the pharmacodynamic (PD) inter action between drugs was assessed with a new modeling approach which i ncludes (a) data transformation to create an essentially error-free X- variable and (b) estimation of an interaction parameter alpha: by fitt ing a nonlinear hyperbolic model to the combination data with unweight ed nonlinear regression. Results, Drug disposition to the biophase was linear within the range of administered doses. The estimates of alpha suggested a Loewe antagonistic interaction between pefloxacin and the ophylline at the induction of maximal seizures in rats. Similar intens ity of PD interaction was observed at the dose and biophase level (alp ha was -0.415 +/- 0.069 and -0.567 +/- 0.079, respectively). Conclusio ns. The suitability of the proposed model was assessed by Monte Carlo simulation. This new mathematical approach enabled the characterizatio n of the Loewe antagonistic nature of the PD (convulsant) interaction between pefloxacin and theophylline, whereas previously used methodolo gies failed to do so.