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 convulsant 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. Cerebrospinal fluid (CSF) and plasma samples were collected for HPLC drug determination. The nature and intensity of the pharmacodynamic (PD) interaction between drugs was assessed with a new modeling approach which includes (a) data transformation to create an essentially error-free X-variable and (b) estimation of an interaction parameter a by fitting a nonlinear hyperbolic model to the combination data with unweighted nonlinear regression.

Results: Drug disposition to the biophase was linear within the range of administered doses. The estimates of a suggested a Loewe antagonistic interaction between pefloxacin and theophylline at the induction of maximal seizures in rats. Similar intensity of PD interaction was observed at the dose and biophase level (alpha was -0.415 +/- 0.069 and -0.567 +/- 0.079, respectively).

Conclusions: The suitability of the proposed model was assessed by Monte Carlo simulation. This new mathematical approach enabled the characterization of the Loewe antagonistic nature of the PD (convulsant) interaction between pefloxacin and theophylline, whereas previously used methodologies failed to do so.