Summary

5-Fluorouracil (5-FU) can significantly increase phenytoin plasma concentrations, potentially leading to phenytoin toxicity. This interaction occurs through inhibition of phenytoin metabolism and requires careful monitoring and possible dose adjustments when these medications are used concurrently.

Introduction

5-Fluorouracil (5-FU) is a pyrimidine analog chemotherapy agent commonly used to treat various solid tumors, including colorectal, breast, and head and neck cancers. It works by inhibiting thymidylate synthase and incorporating into DNA and RNA. Phenytoin is a hydantoin anticonvulsant medication primarily used to treat epilepsy and prevent seizures. It works by blocking voltage-gated sodium channels in neurons, stabilizing neuronal membranes and preventing abnormal electrical activity.

Mechanism of Interaction

The interaction between 5-Fluorouracil and phenytoin occurs primarily through metabolic inhibition. 5-Fluorouracil inhibits the hepatic cytochrome P450 enzyme system, particularly CYP2C9 and CYP2C19, which are responsible for phenytoin metabolism. This inhibition reduces phenytoin clearance, leading to increased plasma concentrations and prolonged half-life. Additionally, 5-FU may compete with phenytoin for protein binding sites, further increasing free phenytoin levels.

Risks and Symptoms

The primary clinical risk of this interaction is phenytoin toxicity, which can manifest as neurological symptoms including ataxia, diplopia, nystagmus, confusion, drowsiness, and slurred speech. Severe toxicity may lead to coma or respiratory depression. The interaction can occur within days to weeks of initiating 5-Fluorouracil therapy and may persist for several weeks after discontinuation due to phenytoin's long half-life. This interaction is considered clinically significant and requires proactive management to prevent adverse outcomes.

Management and Precautions

Close monitoring of phenytoin levels is essential when initiating 5-Fluorouracil therapy in patients taking phenytoin. Baseline phenytoin levels should be obtained before starting chemotherapy, with follow-up levels checked within 1-2 weeks and then regularly throughout treatment. Consider reducing phenytoin dose by 25-50% prophylactically or based on serum levels. Monitor patients closely for signs and symptoms of phenytoin toxicity, including neurological assessments. Alternative anticonvulsants such as levetiracetam or valproic acid may be considered if phenytoin levels become difficult to manage. Healthcare providers should maintain frequent communication and coordinate care between oncology and neurology teams.

Phenytoin interactions with food and lifestyle

Phenytoin has several important food and lifestyle interactions that patients should be aware of. Alcohol consumption can significantly affect phenytoin levels - chronic alcohol use may decrease phenytoin effectiveness by increasing metabolism, while acute alcohol intoxication can increase phenytoin levels and toxicity risk. Patients should discuss alcohol use with their healthcare provider. Enteral nutrition (tube feeding) can significantly reduce phenytoin absorption, requiring dosing adjustments and timing considerations. Folic acid supplementation may decrease phenytoin levels, as phenytoin can cause folate deficiency but supplementation can reduce drug effectiveness. Vitamin D supplementation may be necessary as phenytoin can cause vitamin D deficiency and bone problems. Smoking may increase phenytoin metabolism, potentially requiring dose adjustments. Patients should maintain consistent dietary habits and discuss any significant dietary changes with their healthcare provider, as phenytoin levels can be affected by nutritional status.