Variations in the Blood Phenytoin Levels during Long-Term Combined Treatment with S-1 and Phenytoin

Although combination therapy with the oral fluoropyrimidine anticancer drug S-1 and the anticonvulsant phenytoin (PHT) is known to increase blood levels of PHT and the risk of intoxication, reports on long-term monitoring of blood levels of PHT during combined S-1 and PHT treatment and a thorough understanding of their interaction are lacking. This report aims to describe interactive effects of S-1 and PHT through long-term therapeutic drug monitoring of PHT. A 72-year-old male had been prescribed oral PHT (130 mg/day) for over 20 years and started receiving S-1 therapy (80 mg/day for 4 weeks, followed by a 2-week rest) as postoperative adjuvant chemotherapy for gastric cancer. The blood PHT level was continuously monitored. Prior to receiving S-1, the patient's blood PHT concentration was 6.0 μg/ml, but it increased during S-1 therapy, reaching 22.9 μg/ml on day 84 (during a rest period of second cycle S-1 therapy). After reducing his PHT dosage to 100 mg/day, it never reached toxic levels (4.0-10.4 μg/ml). It was difficult to keep blood PHT concentrations constant because of the time lag between the period of combined use of S-1 and PHT and the timing of manifestation and disappearance of the drug interaction. The DIPS probability scale indicated a highly probable interaction between S-1 and PHT. We conclude that, when S-1 and PHT are used concurrently, occurrence and disappearance time of their interaction need to be predicted to maintain an effective and safe PHT concentration.