The 5,5' diphenylhydantoin (DPH) was synthetized in 1908 and has been used as an antiepileptic drug since 1938. Plasma levels between 10 and 20 mcg/ml are obtained in oral administration of its sodium salt in a dosage of 300 mg per day. I.m. and i.v. administration have no advantages. The drug may be ineffective when its absorption is poor or its metabolism too rapid. Persistence of epileptic attacks in spite of adequate DPH plasma levels indicates severe organic brain damage. Some patients have low DPH tolerance which may be due to congenital enzyme deficiency, metabolic, renal or hepatic disease, or interference by other drugs. Toxic signs are related to the DPH plasma levels: nystagmus at 20 mcg/ml, motor disturbances at 30 mcg/ml, and mental changes at 40 mcg/ml. Side effects involve the nervous, cardiovascular and hemopoietic systems, intestinal tract, kidneys, liver, skin and gums. Occasionally there are behavior disorders, lupus erythematosus, lymphadenopathy, pulmonary changes, polyarthritis, baldness or hirsutism. The biological halflife of DPH is about 15 hr. Maximal excretion occurs 4 to 8 hr after administration. It is metabolized in the liver and about 60 to 70% of the ingested dose is excreted as glucuronate in bile and urine: only 1 to 5% of the dose is excreted unchanged. The concentration of DPH in the brain, especially the cortex, is 2 to 3 times higher than in the plasma. It accumulates also in the liver, pituitary and adrenals. The therapeutic effects of DPH are probably due to late physiological and metabolic changes and occur much later than saturation of the tissues. The hypothalamus pituitary adrenal axis is strongly affected. The release of ACTH, free plasma thyroxine and ADH activity are diminished and water electrolyte balance is upset. It seems that epileptic attacks are caused by a breakdown of inhibition of nerve cell excitability due to electrolyte imbalance. The metabolic effects of DPH include rapid conversion of glutamic acid into gamma aminobutyric acid, which seems to be an important mediator in inhibition of the CNS; decreased content of ACh in the brain; low concentration of folic acid in the plasma; and many other changes. With such a complex picture it is not possible to be sure of the mechanism of its anticonvulsant action.
Rutherfoord Rose, S. (2005). Phenytoin. In Encyclopedia of Toxicology (pp. 405–406). Elsevier. https://doi.org/10.1016/b0-12-369400-0/00756-0