Pharmacokinetic model analysis of interaction between phenytoin and capecitabine.

OBJECTIVE: Recent reports have shbown an increase in serum phenytoin levels resulting in phenytoin toxicity after initiation of luoropyrimidine chemotherapy. To prevent phenytoin intoxication, phenytoin dosage must be adjusted. We sought to develop a pharmacokinetic model of the interaction between phenytoin and capecitabine. METHODS: We developed the phenytoin-capecitabine interaction model on the assumption that fluorouracil (5-FU) inhibits cytochrome P450 (CYP) 2C9 synthesis in a concentration- dependent manner. The plasma 5-FU concentration after oral administration of capecitabine was estimated using a conventional compartment model. Nonlinear pharmacokinetics of phenytoin was modeled by incorporating the Michaelis-Menten equation to represent the saturation of phenytoin metabolism. The resulting model was fitted to data from our previously-reported cases. RESULTS: The developed phenytoincapecitabine interaction model successfully described the profiles of serum phenytoin concentration in patients who received phenytoin and capecitabine concomitantly. The 50% inhibitory 5-FU concentration for CYP2C9 synthesis and the degradation rate constant of CYP2C9 were estimated to be 0.00310 ng/mL and 0.0768 day-1, respectively. This model and these parameters allow us to predict the appropriate phenytoin dosage schedule when capecitabine is administered concomitantly. CONCLUSIONS: This newly-developed model accurately describes changes in phenytoin concentration during concomitant capecitabine chemotherapy, and it may be clinically useful for predicting appropriate phenytoin dosage adjustments for maintaining serum phenytoin levels within the therapeutic range.

[A case of toxicity caused by drug interaction between capecitabine and phenytoin in patient with colorectal cancer].

We present a case of toxicity caused by a drug interaction between capecitabine and phenytoin (PHT). The drug combination elevated the plasma level of PHT in a patient on chemotherapy with capecitabine for colorectal cancer. Our patient was a 44-year-old woman diagnosed with epilepsy in her 20's, being treated with valproic acid (VPA) and PHT. Adjuvant chemotherapy with capecitabine began following surgery for colorectal cancer. Seven weeks later, she developed numbness, dizziness, dysarthria and difficulty walking, and was hospitalized for investigation. Her serum PHT level was elevated at 35. 1 µg/ mL. This case suggests that when capecitabine and PHT are coadministered, PHT levels should be monitored frequently, and that PHT dosage should be adjusted accordingly if it cannot be replaced by an alternative anticonvulsant.