Increased penetration of barbital through the bloodbrain barrier in the rat after pretreatment with probenecid.

Some weak organic acids are eliminated from the brain by an acid transport system. The question arose is this system also used to transport drugs out of the brain? In that case probenecid pretreatment (100 mg/kg subcutaneously) 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 intraperitoneally and in the second experiment barbital (150 mg/kg) was infused intravenously 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 second experiment did probenecid significantly increase the time during which the righting reflex was lost. In the next experiment hexobarbital was infused intravenously at a rate of 0.25 mg/kg/sec. until a burst suppression which lasted 1 sec. or more was seen in a concomitant EEG-record. When this "silent second" occurred the infusion was stopped and the ensuing anaesthesia times recorded. Probenecid had no effect on the induction when studied with this method, but the ensuing anaesthesia times were increased. The hypothesis of an acid transport system out of the brain was thus not refuted by these experimental results. Studies of brain concentrations of barbital also supported this finding. After 200 mg/kg intraperitoneally 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.