Dose-dependent effect of cimetidine on phenytoin kinetics.
Eight normal subjects were given 250 mg intravenous phenytoin alone and with 3-day regimens of oral cimetidine, 400 mg at bedtime, 1200 mg a day, and 2400 mg a day in a randomized crossover fashion. Plasma samples for phenytoin and cimetidine, and urinary concentrations for phenytoin and 5-(4-hydroxyphenyl)-5-phenylhydantoin (HPPH) were measured by HPLC. All cimetidine regimens decreased phenytoin clearance, and there was no difference between the 400-mg bedtime dose and the 1200-mg a day regimens. There was, however, a difference between the 400-mg and 1200-mg and the 2400-mg regimens. There was no linear correlation between steady state cimetidine plasma concentrations and the decrease in phenytoin clearance. Urinary HPPH/phenytoin ratios decreased with all cimetidine treatments, but the differences were not significant. Phenytoin toxicity may result when cimetidine is added to existing regimens of this anticonvulsant.
D000328:Adult; D002851:Chromatography, High Pressure Liquid; D002927:Cimetidine / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004341:Drug Evaluation; D004347:Drug Interactions; D006146:Guanidines / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D008297:Male; D010672:Phenytoin / Q000097:blood / Q000378:metabolism* / Q000652:urine; D011897:Random Allocation
D006146:Guanidines; D010672:Phenytoin; D002927:Cimetidine