Ignoring Pharmacokinetics May Lead to Isoboles Misinterpretation: Illustration with the Norfloxacin-Theophylline Convulsant Interaction in Rats

Abstract

Purpose. To investigate the norfloxacin-theophylline convulsant interaction in vivo, with an experimental approach distinguishing between pharmacodynamics and pharmacokinetics contributions to the observed effect.

Methods. Male Sprague Dawley rats (n = 38) were infused each compound separately or in different combination ratios. Infusion was maintained until the onset of maximal seizures. Cerebrospinal fluid and plasma samples were collected for high performance liquid chromatography drug determination. The nature and intensity of the pharmacodynamics interaction between drugs was quantified with an isobolographic approach.

Results. Isobolograms suggested a relatively marked antagonism between norfloxacin and theophylline at the cerebrospinal fluid (previously shown to be part of the biophase) and dose levels, but not at the plasma (free and total concentrations) levels. These apparent discrepancies could be explained by nonlinear distribution or/and distribution desequilibrium phenomenon.

Conclusions. These findings showed that the quantitative isobolographic approach is appropriate to assess the nature and intensity of the pharmacodynamic interaction between two drugs when data are collected within the biophase, but that data interpretation outside the biophase can be risky due to further pharmacokinetic complexities, in particular slow or/and nonlinear diffusion into the biophase.