Kinetics of drug action in disease states. IX. Effect of experimental fever on phenobarbital concentrations at onset of loss of righting reflex in rats.

The purpose of this investigation was to determine the effect of fever on the concentration-pharmacologic activity relationship of phenobarbital (PB). Fever was produced in adult female Lewis rats by either bacterial endotoxin or brewer's yeast. Endotoxin elevated body temperature by 0.9 +/- 0.6 degrees C in one study and by 1.0 +/- 0.4 degrees C in another. Brewer's yeast caused a more pronounced and protracted elevation of temperature averaging 1.8 +/- 0.3 degrees C at the time of the pharmacodynamic measurements. PB was administered by slow i.v. infusion until the rats lost their righting reflex. The concentrations of PB at that time in serum, cerebrospinal fluid and brain were appreciably lower in the hyperpyrexic than in control (saline-treated) animals, irrespective of the method used to produce fever. Thus, fever is associated with an increased sensitivity of the central nervous system to the depressant effect of PB. This observation may be of particular relevance to the use of PB for the treatment and prevention of febrile convulsions.