LETTER TO THE EDITOR

Interaction between warfarin and S-fluorouracil, not between warfarin and levamisole To the Editor:

The article by Wehbe and Warthl relates the case of a woman in whom a medication interaction developed that involved warfarin and the combination of 5fluorouracil and levamisole. The interaction involved a prolongation of the prothrombin time (PT), with a resultant episode of bleeding. The PT became maximally prolonged 18 days after the start of combination therapy but only 4 days after the start of a course of levamisole alone. Because of the proximity of the PT prolongation to the administration of levamisole, the authors concluded that the PT prolongation was caused by an interaction between warfarin and levamisole.

I disagree with this conclusion and propose that the patient’s PT prolongation was caused by an interaction between war- farin and 5fluorouracil. There have been 3 other published case reports that involve an interaction between warfarin and a chemotherapy regimen based on 5-fluorouracil. In the first report, the patient’s PT became maximally prolonged 8 days after the start of a regimen consisting solely of 5-fluorouracil.2 In the second report, the patient’s PT became prolonged 4 weeks after the start of a regimen of 5fluorouracil and lev- amisole.3 In the third report, the patient’s PT became maxi- mally prolonged 4 weeks after the start of a regimen of 5-flu- orouracil and leucovotin calcium (INN, calcium folinate).4

In the case reported by Wehbe and Warth, the delay in the prolongation of the PT is consistent with the pattern estab- lished in the other case reports. In addition, there is more data

to suggest an interaction between warfarin and 5-fluorouracil than between warfarin and levamisole. Although the interac- tion between 5-fluorouracil and warfarin is speculative, its existence is supported by a case report suggesting an interac- tion between 5-fluorouracil and phenytoins (which is metab- olized by the same enzyme that metabolizes warfarin).

Thus, in the case reported by Drs. Wehbe and Warth, it seems probable that the PT prolongation was caused by the interaction between warfarin and 5-fluorouracil and not between warfarin and levamisole.

Michael C. Brown, MD Division of Gastroenterology

University of Washington Medical Center Seattle, Wash.

References 1. Wehbe TW, Warth JA. A case of bleeding requiring hospitaliza-

tion that was likely caused by an interaction between warfarin and levamisole. Clin Pharmacol Ther 1996;59:360-2.

2. Wajima T, Mukhopadhyay P Possible interactions between war- farin and 5-fluorouracil [letter]. Am J Hematol 1992;40:238.

3. Scarfe MA, Israel MK. Possible drug interaction between war- farin and combination of levamisole and fluorouracil. Ann Phar macother 1994;28:464-7.

4. Brown MC. Multisite mucous membrane bleeding due to a pos- sible interaction between warfarin and 5-fluorouracil. Pharma- cotherapy 1997;17:631-3.

5. Wakisaka S, Shimauchi M, Kaji Y, Nonaka A, Kinoshita K. Acute phenytoin intoxication associated with the antineoplastic agent UFT. Fukuoka Igaku Zasshi 199O;Sl: 192-6.

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