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Plasma concentrations of phensludmide, methsuximide, and their metabolites in relation to clinical efficacy

Clinical Epilepiqy Section, Experimental Therapeutics Branch and the Epilepsy Branch, National 1nstit.ute of Neurological and Communicative Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.

The clinical efficacy of phensuximide and methsuximide was studied in relation to plasma concentrations of these compounds and their desmethyl metabolites. Single- and chronic-dose studies of each drug were carried out in five patients with intractable seizures. Patients were evaluated before and during treatment by 6-hour simultaneous video and telemetered electroencephalographic recordings to characterize the seizure type and by daily determinatiions of plasma antiepileptic drug concentrations. Phensuximide had a mean half-life of 7.8 hours and accumulated to an average fasting level ofonly 5.7 pg per milliliter. Desmethylphensuximide averaged only 1.7 pg per milliliter with a similar half-life. Methsuximide had an even shorter half-life, averaging 1.4 hours, but its desmethyl metabolite had a mean half-life of 38 hours and therefore accumulated to levels in excess of 40 pg per milliliter. The addition of phensuximide to their regimens benefited none of the patients, but two had an excellent response to methsuximide. The failure of phensuximide and its desmethyl metabolite to accumulate to reasonable levels is the likely explanation for the relatively weak antiepileptic effect of phensuximide as compared with methsuximide.

Dr. Porter's address is Epilepsy Branch, Federal Building, Room 114, National Institutes of Health, Bethesda, MD 20205.

Presented in part at the twenty-ninth annual meeting of the American Academy of Neurology, Atlanta, Georgia, April 1977.

Accepted for publication April 6, 1979.

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