EFFECT OF LIVER INJURY AND NEPHRECTOMY ON THE ANTICONVULSANT ACTIVITY OF CLINICALLY USEFUL HYDANTOINS

¹ Departments of Pharmacy and Pharmacology, University of Utah College of Pharmacy and College of Medicine, Salt Lake City, Utah

Dilantin, Mesantoin and Thiantoin were tested at various intervals after their administration in normal, nephrectomized and liver-injured rats for their ability to prevent the tonic extensor component of maximal electroshock seizures. The results were analyzed for the effect of liver injury and nephrectomy on the anticonvulsant potency and the duration of action of these compounds. Liver injury significantly increases both the anticonvulsant potency and the duration of action of Mesantoin and Thiantoin, but increases only the potency of Dilantin. On the other hand, bilateral nephrectomy increases the anticonvulsant potency and the duration of action only of Thiantoin, and has no significant effect on the anticonvulsant properties of Dilantin and Mesantoin. Indirect but nevertheless strong evidence suggests that the liver is the principal organ for the degradation of Mesantoin to products devoid of anticonvulsant action, and that the kidney plays no important role in the metabolic alteration or excretion of this compound. In contrast, both the liver and the kidney appear to be concerned in the breakdown and elimination of Thiantoin, the liver occupying the more important role. The possible mechanisms by which liver injury increases the anticonvulsant potency of Dilantin without prolonging its duration of action are discussed. Certain clinical implications of the findings are presented. The results of this report validate the use of biological methods for the study of the fate and the excretion of antiepileptic hydantoins and warrant a similar examination of therapeutically useful anticonvulsants from other chemical series.

This article has been cited by other articles:

				R. G. SLAVIN and G. O. BROUN JR. Agranulocytosis After Diphenylhydantoin and Chlorothiazide Therapy: A Case Report and Discussion of the Evidence for the Primary Role of Diphenylhydantoin Arch Intern Med, December 1, 1961; 108(6): 940 - 944. [Abstract] [PDF]