Probable metabolic interaction of doxifluridine with phenytoin.

Objective: To report the marked elevation of the serum phenytoin concentration during treatment with antineoplastic agents.

Case Summary: A 51-year-old Japanese woman, who was diagnosed with multiple brain metastatic tumors, was placed on oral phenytoin at a maintenance dose of 200 mg/d (3.8 mg/kg/d) to prevent seizures. The serum concentration of phenytoin was well controlled within the therapeutic range; no seizures occurred. Four months later, combination therapy with doxifluridine (5'-DFUR) 800 mg/d, cyclophosphamide 100 mg/d, and medroxyprogesterone acetate 800 mg/d was initiated because of further metastasis. Approximately 1 month after the start of concurrent treatment with the antineoplastic agents, the serum phenytoin concentration was elevated to fourfold of the original concentration. Staggering was observed at that time, but toxic symptoms gradually subsided with the decline in the serum phenytoin concentration after its withdrawal.

Discussion: A probable explanation for the marked elevation of serum phenytoin concentration is a reduction of the capacity of CYP2C-dependent phenytoin metabolism, and the antineoplastic agents could be involved in this event. The interaction of fluorouracil and phenytoin is known in clinical practice, and it is reported that the expression of hepatic CYP2C enzymes is depressed by exposure of rats to fluorouracil. 5'-DFUR, a prodrug of fluorouracil, was considered the likeliest candidate responsible for the interaction. This interaction was of clinical significance because of the great extent of changes in the serum phenytoin concentration.

Conclusions: Clinicians should be aware of the elevation of serum phenytoin concentrations when phenytoin is given in combination with fluorouracil derivatives, including 5'-DFUR.