CIMETIDINE-PHENYTOIN INTERACTION - EFFECT ON SERUM PHENYTOIN CONCENTRATION AND ANTIPYRINE TEST

In 9 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 3 wk on cimetidine (P < 0.01), and fell to 5.8 .+-. 1.2 mg/l within 2 wk after withdrawal of cimetidine. The protein binding of phenytoin was not changed by cimetidine. After use of phenytoin for 2-4 mo., antipyrine clearance increased from 0.67 .+-. 0.06 ml/min per kg to 1.61 .+-. 0.22 ml/min per kg, and antipyrine half-life fell from 10.9 .+-. 1.3 h to 4.5 .+-. 0.6 h as compared to the values before phenytoin treatment (P < 0.01). After 3 wk combined use of cimetidine and phenytoin, antipyrine clearance was decreased to 1.01 .+-. 0.007 ml/min /kg and antipyrine half-life was prolonged to 6.1 .+-. 0.5 h, (P < 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 cimetidine was 2.8 .+-. 0.3 h in the patients on long-term phenytoin treatment. There was a significant positive correlation (P < 0.001) between the increase in serum phenytoin concentration and the prolongation of antipyrine half-life caused by cimetidine. Cimetidine increases serum phenytoin concentration, probably by inhibiting its metabolism. Care should be taken in the concomitant use of cimetidine and phenytoin, and the dose of phenytoin should be modified according to the clinical symptoms and serum phenytoin concentrations.