Ticlopidine inhibits phenytoin clearance

Because cases of phenytoin toxicity during concomitant ticlopidine therapy have been reported, we investigated the effects of multiple doses of ticlopidine on phenytoin pharmacokinetics in six patients receiving phenytoin monotherapy. Two steady-state dosing rate and serum phenytoin minimum concentration (C(min)) pairs were obtained for each patient administered oral phenytoin alone, then phenytoin plus 250 mg ticlopidine twice daily. All patients had serum C(min) ticlopidine values of 0.06 to 0.25 μg/mL when receiving ticlopidine. Individual pharmacokinetic parameters for phenytoin were calculated. The Michaelis-Menten constant (K(m)) was determined as the slope and maximum velocity (V(max); equivalent to the maximal rate of elimination or the maximum daily dose that can be metabolized) as the y- intercept of the linear Michaelis-Menten plot. Mean phenytoin K(m) significantly increased from 5.8 to 12.3 during ticlopidine coadministration compared with administration of phenytoin alone (P = .02). Mean phenytoin V(max) was not significantly changed by the coadministration of ticlopidine. These data indicate that ticlopidine inhibits the clearance and alters the clinical pharmacokinetics of phenytoin so that dosage adjustment of phenytoin should be considered when ticlopidine is coadministered. The results are consistent with previous human liver microsome findings that ticlopidine is a potent inhibitor of CYP2C19, a P450 isozyme that is significantly responsible for phenytoin metabolism.