Effect of diphenylhydantoin on hepatic drug hydroxylation

Two experiments were done on eight males who were to receive diphenylhydantoin (DPH) for epilepsy: the metabolic disposition of phenazone (antipyrine, 14 mg/kg p.o.) was examined before and after 2.5–6 months of treatment with DPH (300 mg/day). The average half-life of phenazone fell from 10.0 h in the first study to 6.1 h after DPH treatment; and the urinary excretion of unchanged phenazone decreased within 24 h from 28.5 mg (2.8% of the dose) to 18.1 mg (1.8% of the dose). Similar results were obtained when data were calculated on the basis of the output of creatinine. The amount of 4-OH-phenazone, the principal hydroxylated metabolite excreted in the urine in the 24 h after dosing, increased from 185 mg (18% of the dose) to 300 mg (29.5% of the dose) during treatment with DPH. In an additional epileptic patient, who suffered from Icterus juvenilis Meulengracht, the half-life of phenazone decreased from 20.7 h to 6.6 h after 22 days treatment with DPH (300 mg/day); the serum bilirubin concentration fell from 2.6 mg% to 1.0 mg% during the same period. The results are considered to show increased activity of hepatic microsomal drug hydroxylating systems, which can be attributed to treatment with DPH for several weeks.