Diphenylhydantoin: disposition and effects of administration on hepatic function in guinea pigs.

Abstract

Diphenylhydantoin sodium (phenytoin; DPH) was administered per os to fasted and non-fasted male and female albino guinea pigs either as single doses or as daily doses for 3 consecutive days. Pharmacokinetic studies involved measurement of the serum and alimentary DPH residues by gas–liquid chromatography following solvent extraction. The transit time of barium meal in the alimentary tract was studied by fluoroscopy in both fasted and nonfasted animals. Animals were killed 24 h following three consecutive daily doses of DPH (25 mg/kg body weight) and in vitro measurements of hepatic microsomal p-nitroanisole O-demethylase (OD), aniline hydroxylase (AH), NADPH-cytochrome c reductase (NADPH-CcR), nonspecific carboxylesterase, and UDPglucuronosyltransferase activities were made.Severe toxicity and sedation were observed at doses of 100 and 50 mg/kg body weight, respectively. No overt signs were observed at a dose of 25 mg/kg body weight, this dosage being selected for futher study. The apparent β-phase t0.5 of serum DPH following a single oral dose of 25 mg/kg body weight was approximately 6.5 h in nonfasted guinea pigs. Initial peak serum levels of DPH were observed at 2 h in fasted and nonfasted animals and secondary peak levels were observed at 12 h in nonfasted and at 24 h in fasted animals. There was a good correlation between the rate of DPH absorption, fasting state, and alimentary transit time. In animals receiving 25 mg DPH/kg body weight orally for 3 consecutive days, there was marked induction of hepatic OD, AH, and NADPH-CcR. No changes were observed in nonspecific carboxylesterase or UDPglucuronosyltransferase activities. The major metabolite of DPH, 5-(p-hydroxyphenyl)-5-phenylhydantoin (HPPH), was not detected in the tissue in sufficient quantities to exert an influence on monooxygenase activities.