Phenytoin toxicity as a result of 5-fluorouracil administration is not readily reported in the literature. Reported here is a 50-year-old woman presenting with signs of phenytoin toxicity after commencing 5-fluorouracil therapy for rectal cancer.

This 50-year-old female was diagnosed with node positive carcinoma of the rectum after experiencing abdominal pain and bleeding per rectum. Following an AP resection she commenced adjuvant 5-fluorouracil (5-FU) chemotherapy according to an established post operative schedule (Table 1).1

Her past medical history included generalised seizures and a hysterectomy. The epilepsy had been well controlled on phenytoin and she had not experienced a seizure for more than five years. Her medication regimen included premarin 1.25mg once daily and phenytoin 100 mg mane and 200 mg nocte. She had her phenytoin level checked six monthly and reported that she was normally well controlled and experienced no difficulties with her anti-epileptic medication. Having completed the first two cycles of chemotherapy (refer to schedule above), the patient reported a one week history of unsteadiness and blurring of vision. She had no headache or vertigo, had not collapsed or had a seizure. She had continued with her normal doses of medications and had not vomited or been otherwise unwell.

On examination the patient was very unsteady on standing and markedly ataxic, needing to hold on to a hand rail to walk. Cardiovascular and respiratory examinations were normal. Neurological examination revealed sustained bilateral rotational and horizontal nystagmus on lateral gaze. There were no sensory, tone or power deficits in her limbs. Reflexes were also normal with down going plantar reflexes. Coordination was impaired bilaterally with the patient unable to successfully complete finger-nose-finger and heel-shin tests.

Serum biochemistry and haematology values were all normal. Her phenytoin level, however, was 188 umol/L (therapeutic range 40–80 umol/L).

Having stopped the phenytoin, the patient later developed a subclavian vein thrombosis around a newly inserted PICC line. She was anticoagulated with daily low molecular weight heparin. Warfarin was not used, in the hope of avoiding further pharmacological interactions.

Phenytoin is metabolised by CYP2C9, a component of the cytochrome p450 group of enzymes. Secondary metabolism with CYPC19 also occurs. The metabolite 5-(p-hydroxyphenyl)-5-phenylhydantoin (HPPH) is then conjugated and the clinically inactive metabolites are excreted in the urine.2

The elimination pharmacokinetics of phenytoin are first order at lower serum levels. Once serum concentrations increase, even within the therapeutic range, metabolic mechanisms are saturated and elimination becomes dose dependent.

5-FU is an antimetabolite, and can be catabolised by dihydropyrimidine dehydrogenase (DPD) to inactive dihydrofluorouracil or be metabolised to form active nucleotide metabolites. DPD activity is the rate limiting step in 5-FU catabolism. A deficit of DPD correlates with significantly enhanced 5-FU toxicity.3

It seems likely that 5-FU inhibits CYP2C9 and thereby decreases phenytoin clearance4. This may then result in previously well controlled patients suddenly exhibiting symptoms of phenytoin toxicity. Phenytoin toxicity secondary to 5-FU, however, has not been widely reported. Cerebellar toxicity has been associated with 5-FU, however it is usually associated with other toxicities such as stomatitis or diarrhoea.

Applying the adverse drug reaction probability scale proposed by Naranjo et al,5 this proposed interaction between 5-FU and phenytoin has a total score of 5, indicating a probable causal relationship. Patients receiving phenytoin and 5-FU (or its analogues) are at risk of developing toxicity and may therefore benefit from closer monitoring of serum phenytoin levels and observation for early signs of phenytoin toxicity.

Author information: Ian Rosemergy, Medical Registrar, Hutt Hospital; Michael Findlay, Medical Oncologist, Wellington Cancer Centre, Wellington Hospital, Wellington

Correspondence: Dr Michael Findlay, Wellington Cancer Centre, Capital Coast Health, Wellington. Fax: (04) 385 5984; email: michael.findlay@cdhb.org.nz