STUDIES ON THE METABOLISM OF DIPHENYLHYDANTOIN IN MICE

¹ Department of Medicine (Division of Clinical Pharmacology), The Johns Hopkins University School of Medicine, Baltimore, Maryland

The rate of disappearance of diphenylhydantoin (DPH) has been measured in mice given different doses ranging from 125 g to 1250 g. The biologic half-life (T) of DPH in mice increases as the dose increases and ranges from 5 hr in mice given 125 g each to 16 hr in mice given 1 mg each. The rate of disappearance of DPH does not follow first-order kinetics in five of the six doses studied. An increase in the rate of disappearance of DPH in mice given 1 mg occurs after 16 hr. The increase in rate is associated with a stimulation of the drug-metabolizing liver microsomal enzymes. Treatment of mice with a single dose of 1 mg of DPH results in a significant increase in liver microsomal protein, zoxazolamine hydroxylase activity and cytochrome P450 content. Treatment of mice with 1 mg of DPH daily for 4 days also increases liver weight and liver protein and causes a proliferation of the smooth endoplasmic reticulum. A subsequent dose of 1 mg of DPH is metabolized more rapidly in these mice (T = 7.5 hr) compared with controls ( T = 16 hr), and the disappearance more closely follows first-order kinetics. Four days of treatment of each mouse with 1 mg daily of DPH results in a reduction in hexobarbital sleeping time and zoxazolamine paralysis time 40 hr after the last injection of DPH. There is also increased hexobarbital oxidase activity and zoxazolamine hydroxylase activity in liver microsomes of these mice. SKF 525-A (-diethylaminoethyl diphenylpropyl acetate) (50 mg/kg) and cycloheximide (100 mg/kg) pretreatment decreases the rate of disappearance of DPH.