Cimetidine-phenytoin interaction: effect on serum phenytoin concentration and antipyrine test

In a prospective study in nine patients the effects of phenytoin and of cimetidine (1000 mg/day) + phenytoin on the antipyrine test and serum phenytoin concentrations were studied. Serum phenytoin increased from the steady state level of 5.7 +1.3 mg/l to 9.1 +1.4 mg/l after three weeks on cimetidine (p less than 0.01), and fell to 5.8 +1.2 mg/l within two weeks after withdrawal of cimetidine. The protein binding of phenytoin was not changed by cimetidine. After use of phenytoin for 2-4 months, antipyrine clearance increased from 0.67 +0.06 ml/min/kg to 1.61 +0.22 ml/min/kg, and antipyrine half-live fell from 10.9 +1.3 h to 4.5 +0.6 h as compared to the values before phenytoin treatment (p less than 0.01). After three weeks combined use of cimetidine and phenytoin, antipyrine clearance was decreased to 1.01 +0.07 ml/min/kg and antipyrine half-life was prolonged to 6.1 +0.5 h, (p less than 0.01) compared to the values on phenytoin alone. The distribution volume of antipyrine was not affected by phenytoin nor by cimetidine + phenytoin. The half-life of cimetidine was 2.8 +0.3 h in the patients in the longterm phenytoin treatment. There was a significant positive correlation (p less than 0.001) between the increase in serum phenytoin concentration and the prolongation of antipyrine half-life caused by cimetidine. Thus, cimetidine increases serum phenytoin concentration, very probably by inhibiting its metabolism. Care should be taken in the concomitant use of cimetidine ad phenytoin, and the dose of phenytoin should be modified according to the clinical symptoms and serum phenytoin concentrations.