Caffeine as a potential risk factor for theophylline neurotoxicity

Theophylline can cause life-threatening seizures when administered in excessive doses. The plasma concentrations associated with this neurotoxic effect vary widely among patients. To determine the reasons for the wide variation, an animal model of theophylline-induced seizures was developed and has now been used to determine the effect of pre-exposure to caffeine on theophylline-induced neurotoxicity. Male adult rats received an iv infusion of either caffeine citrate or sodium citrate solution for 15 min. Theophylline was then infused at a relatively rapid rate until onset of maximum seizures. A third group of rats received a rapid infusion of caffeine only until onset of seizures. Samples of blood, brain, and cerebrospinal fluid were obtained at that time for determination of caffeine and theophylline concentrations by HPLC. Prior exposure to caffeine was associated with a statistically significant reduction in the total amount of theophylline required to produce seizures and caused theophylline concentrations at all sampling sites to be significantly lower than in controls. Caffeine alone required a larger total dose and higher concentrations than theophylline alone to produce seizures. It is concluded that acute exposure to caffeine can increase the risk of theophylline-induced neurotoxicity.