Dose-dependent effect of cimetidine on phenytoin kinetics

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Abstract
Normal subjects [8] were given 250 mg i.v. phenytoin alone and with 3-day regimens of oral cimetidine, 400 mg at bedtime, 1200 mg/day, and 2400 mg/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 [high performance liquid chromatography]. All cimetidine regimens decreased phenytoin clearance, and there was no difference between the 400-mg bedtime dose and the 1200 mg/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.