Accelerated metabolism of probenecid during long-term treatment of rats with anticonvulsant drugs: effect on central serotonin turnover studies

Abstract

Studies were carried out in rats to determine the effects of long-term administration (once daily for 9 days) of phenytoin (50 mg kg −1), sodium phenobarbital (25 mg kg −1), primidone (50 mg kg −1), and l-5-hydroxytryptophan ( l-5-HTP; 50 mg kg −1) on probenecid metabolism and on serotonin turnover rates as estimated by probenecid-induced accumulation of 5-hydroxyindoleacetic acid (5-HIAA) in brain. Without probenecid, mean brain 5-HIAA levels were similar in control and drugtreated rats, suggesting that the turnover rate of brain serotonin was not affected by the chronic anticonvulsant drug pretreatment. But, in the rats treated with phenobarbital, the rate of accumulation of 5-HIAA in brain during the first 90 min after probenecid (200 mg kg −1) was significantly lower than the rate of accumulation in the control rats. Also, at 6 hr after probenecid, brain 5-HIAA levels were similar to pre-probenecid values in the rats pretreated with phenobarbital or primidone, while 5-HIAA levels were still increased in the rats treated with phenytoin, l-5-HTP, or vehicle. Examination of serum revealed that the concentration of probenecid in serum decreased more rapidly in rats pretreated with either primidone or phenobarbital than in rats given vehicle, l-5-HTP, or phenytoin. It is likely, therefore, that the decreased 5-HIAA accumulation in the brains from these animals were due to decreased inhibition of 5-HIAA efflux and not to a decreased rate of serotonin turnover in brain. Since a sustained inhibition of acid transport by probenecid is required, drug interactions with probenecid may be important in clinical studies using probenecid-induced accumulations of 5-HIAA in cerebrospinal fluid to estimate central serotonin turnover rates.