Kinetics of drug action in disease states. XXVI: Effect of fever on the pharmacodynamics of theophylline-induced seizures in rats.

This investigation was designed to determine the effect of fever on the neurotoxicity of theophylline as reflected by the concentrations of this drug that cause convulsions in experimental animals. Fever was produced in male, inbred, adult Lewis rats (approximately 180 g) by sc injection of brewer's yeast; an elevation of body temperature of 1.2 +/- 0.4 degrees C (mean +/- SD) was achieved at the time of the pharmacodynamic measurements. Theophylline was infused iv at a rate of 1.03 mg/min until the onset of maximal seizures. Drug concentrations in serum, serum water, brain, and cerebrospinal fluid (CSF) at that time were determined by high-performance liquid chromatography. Compared with the control group, the group of febrile rats had statically significantly lower serum protein concentrations, decreased serum protein binding of theophylline, and slightly increased theophylline concentrations in the CSF at the onset of seizures. Inasmuch as theophylline concentrations in the CSF reflect the concentrations of this drug in the biophase, the results of this study show that fever does not increase the sensitivity of the central nervous system to the neurotoxic effects of theophylline in rats. In fact, a statistically significant positive correlation between theophylline concentrations in the CSF and body temperature was found in this investigation, suggesting a decreased sensitivity of the animals to the neurotoxic effects of theophylline at higher body temperature.