A complex interaction between clozapine and phenytoin

Objective: As of July 9, 2004, to report the first case of potential pharmacodynamic and pharmacokinetic interactions between clozapine and phenytoin occurring simultaneously in a patient. Case Summary: A 60-year-old African American female treated with clozapine and phenytoin developed neutropenia after the clozapine dose was increased from 650 to 900 mg/day. The neutropenia resolved after phenytoin was discontinued, and the clozapine dose was decreased from 900 to 300 mg/day without any significant change in clozapine levels. Discussion: Neutropenia can be explained on the basis of a potential pharmacodynamic interaction between clozapine and phenytoin. However, neutropenia did not occur until the clozapine dose was increased from 650 to 900 mg/day, corresponding to an increase in clozapine levels from 90 to 114 ng/mL. Neutropenia resolved after phenytoin was discontinued, even though the clozapine concentrations achieved after phenytoin discontinuation (137 ng/mL) were almost the same as those when phenytoin was coadministered (114 ng/mL). This finding suggests that neutropenia was precipitated not only by an increase in the clozapine dose, but also by the concomitant use of phenytoin. On the other hand, the decrease in clozapine concentrations can be explained on the basis of a pharmacokinetic interaction between clozapine and phenytoin. Phenytoin has the potential to decrease clozapine concentrations by inducing the activity of CYP1A2, which provides a primary metabolic pathway for clozapine. Conclusions: Concomitant use of phenytoin may not only decrease clozapine concentrations and compromise its efficacy, but can also precipitate neutropenia. Although based on a single case report, these findings warrant caution when coadministering clozapine and phenytoin.