Increased Penetration of Barbital through the Bloodbrain Barrier in the Rat after Pretreatment with Probenecid

Abstract

Some weak organic acids are eliminated from the brain by an acid transport system. Is this system also used to transport drugs out of the brain? In that case probenecid pretreatment (100 mg/kg s.c.) should influence the induction time of a slightly lipid soluble barbiturate (barbital), which penetrates into the brain slowly, more than the induction time of a very lipid soluble barbiturate (hexobarbital). In the first experiment barbital (200 mg/kg) was given i.p. and in the 2nd experiment barbital (150 mg/kg) was infused i.v. during 10 min. In both experiments loss of righting reflex occurred more rapidly after pretreatment with probenecid compared with pretreatment with saline. Only in the 2nd experiment did probenecid significantly increase the time during which the righting reflex was lost. In the next experiment hexobarbital was infused i.v. at a rate of 0.25 mg/kg per s until a burst suppression which lasted 1 s or more was seen in a concomitant EEG-record. When this silent second occurred the infusion was stopped and the ensuing anesthesia times recorded. Probenecid had no effect on the induction when studied with this method, but the ensuing anesthesia times were increased. The hypothesis of an acid transport system out of the brain was not refuted by these experimental results. Studies of brain concentrations of barbital also supported this finding. After 200 mg/kg i.p. the concentration of barbital in the brain was higher after pretreatment with probenecid as compared to saline pretreated controls, i.e., at times corresponding to the induction times in the in vivo experiments. No difference was found in the serum levels of barbital.