Ticlopidine inhibition of phenytoin metabolism mediated by potent inhibition of CYP2C19

A patient who had taken a stable dose of phenytoin for 2 years had a coronary stent placed for unstable angina and ticlopidine was added to his therapeutic regimen. Twenty-five days later, he was hospitalized with acute symptomatic phenytoin toxicity and a serum concentration of 46.5 mu g/ml. Determination of metabolic genotype revealed that the patient had a wild-type genotype for CTP2C9, CTP2C19, and CTP2D6. Using human liver microsomes, we showed that ticlopidine is a potent inhibitor of cytochrome P450 2C19, with an estimated inhibition constant (K-i) of 3.7 +/- 0.2 mu mol/L. The influence of ticlopidine on CYP2C9, the other cytochrome P450 isoform that metabolizes phenytoin, is relatively weak, with a calculated K-i of 38.8 +/- 27 mu mol/L. These data suggest that, in this patient, phenytoin toxicity was caused by inhibition of CYP2C19 by ticlopidine, and the data emphasize the importance of CYP2C19 in the metabolism of phenytoin.