Abstract

After oral administration of primidone (3.9-500 mg/kg) to rats, plasma and brain levels of the drug and its metabolites, phenobarbital and phenylethylmalonamide (PEMA), were analyzed by gas-liquid chromatography and susceptibility to seizures induced by hexafluorodietiyl ether (flurotlhyl), pentylenetetrazol (Metrazol) and maximal electroshock (MES) were measured at 0.5 to 24 hours after dosage. Plasma levels of primidone peaked at 1 hour whereas brain levels peaked at 2 hours. The time course of protection against flurothyl and pentylenetetrazol seizures was more closely related to the appearance of phenobarbital and PEMA in brain than to that of primidone. At dose levels when only primidone was detectable in brain, protection against flurothyl or pentylenetetrazol seizures was minimal or absent whereas complete protection against MES was observed at brain and plasma levels of primidone as low as 1 µg/g (ml) or less. In contrast, 60 minutes after i.p. injection of authentic phenobarbital or PEMA in the absence of primidone, brain levels of 9 µg/g of phenobarbital or 95 µg/g of PEMA were required to completely protect against MES. It was concluded that primidone possesses independent anticonvulsant activity and is more potent than phenobarbital with respect to MES. Further, based on brain concentration, primidone and phenobarbital are considerably more effective anticonvulsants than PEMA.