Kinetics of drug action in disease states. XIII. Effect of dialyzable component(s) of uremic blood on phenobarbital concentrations in rats at onset of loss of righting reflex.

The purpose of this investigation was to determine if the previously demonstrated increased sensitivity of the central nervous system of uremic rats to the hypnotic activity of phenobarbital is caused, wholly or in part, by the accumulation of one or more endogenous substances. Blood was obtained from normal donor rats and from rats made uremic by administration of uranyl nitrate 5 days earlier. The serum was dialyzed against water, using a cellophane membrane with a molecular exclusion limit of 12,000 to 14,000 daltons, and the dialysate was lyophilized. A concentrate of the dialysate was administered by i.v. infusion to normal rats who also received a slow i.v. infusion of phenobarbital until they lost their righting reflex. Samples of cerebrospinal fluid, blood (for serum) and the brain were obtained at that time and were assayed for phenobarbital. Compared to the two control groups, i.e., rats infused with serum dialysate from normal animals or with normal saline solution, rats infused with serum dialysate from uremic rats lost their righting reflex at significantly lower phenobarbital concentrations in serum, brain and cerebrospinal fluid. This shows that the serum of uremic rats contains appreciable concentrations of one or more dialysable components capable of potentiating or contributing to the hypnotic activity of phenobarbital.