Relationships between plasma concentrations of diphenylhydantoin, phenobarbital, carbamazepine, and 3-sulfamoylmethyl-1,2-benzisoxazole (AD-810), a new anticonvulsant agent, and their anticonvulsant or neurotoxic effects in experimental animals

Abstract

The relationships between plasma concentrations of diphenylhydantoin (DPH), phenobarbital (PB), carbamazepine (CBZ), and 3-sulfamoylmethyl-1,2-benzisoxazole (AD-810), a new anticonvulsant agent, and their anticonvulsant and neurotoxic effects were studied in various species of animals. Anticonvulsant activities of test drugs were examined by the maximal electroshock seizure (MES) test. Neurotoxicities were determined by the rotorod performance test in mice and rats and by behavioral observations in rabbits, dogs, and monkeys. It was demonstrated that both the anticonvulsant effects and the neurotoxic effects of the drugs tested were more closely correlated with their plasma concentrations than with the dosages administered. There was a critical plasma concentration for each drug to show an anticonvulsant effect or to cause a neurotoxic effect in an individual animal. The critical plasma concentrations for anticonvulsant and neurotoxic effects of each drug were relatively constant among different species, with the exception of DPH in rabbits, which had twice the value in other species. The therapeutic ranges of plasma concentrations of DPH, PB, and CBZ determined in various species of animals coincided well with those recommended clinically. AD-810 was found to be effective against MES without signs of neurological toxicity in the ranges of plasma concentrations of 9.8 to 74.0, 10.8 to 95.0, 9.6 to 117.0, and 12.6 to 96.2 microgram/ml in mice, rats, rabbits, and dogs, respectively. These results seem to suggest that AD-810 may be effective clinically at plasma concentrations above 10 microgram/ml, with a therapeutic range up to 70 microgram/ml, which is much wider than the therapeutic ranges of DPH (10--20 microgram/ml), PB (10--30 microgram/ml), and CBZ (4--10 microgram/ml).