Ticlopidine inhibits phenytoin clearance

Because cases of phenytoin toxicity during concomitant ticlopidine therapy have been reported, we investigated the effects of multiple doses of ticlop idine on phenytoin pharmacokinetics in six patients receiving phenytoin mon otherapy, Two steady-state dosing rate and serum phenytoin minimum concentr ation (C-min) pairs were obtained for each patient administered oral phenyt oin alone, then phenytoin plus 250 mg ticlopidine twice daily. All patients had serum C-min ticlopidine values of 0.06 to 0.25 mu g/mL when receiving ticlopidine, Individual pharmacokinetic parameters for phenytoin were calcu lated. The Michaelis-Menten constant (K-m) was determined as the slope and maximum velocity (V-max; equivalent to the maximal rate of elimination or t he maximum daily dose that can be metabolized) as the y-intercept of the Li near Michaelis-Menten plot. Mean phenytoin K-m significantly increased from 5.8 to 12.3 during ticlopidine coadministration compared with administrati on of phenytoin alone (P = .02), Mean phenytoin V-max was not significantly changed by the coadministration of ticlopidine. These data indicate that t iclopidine inhibits the clearance and alters the clinical pharmacokinetics of phenytoin so that dosage adjustment of phenytoin should be considered wh en ticlopidine is coadministered, The results are consistent with previous human liver microsome findings that ticlopidine is a potent inhibitor of CY P2C19, a P450 isozyme that is significantly responsible for phenytoin metab olism.