Inhibition of Fluorouracil Catabolism in Cancer Patients by the Antiviral Agent (E)-5-(2-bromovinyl)-2'-deoxyuridine

The thymidine analogue (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVdUrd), which is an antiviral agent effective against herpes simplex virus type 1 and varicella zoster virus, has also proved to be a potent inhibitor of dihydrouracil dehydrogenase, the major degrading enzyme of the anticancer drug fluorouracil (FUra). To evaluate the effect of BVdUrd on the pharmacokinetics of FUra in cancer patients, BVdUrd was administered orally at a daily dose of 250 mg (five patients) or 3 x 250 mg (five patients). FUra was infused at doses of 110-400 mg over 10 min. Blood and urine samples were collected regularly during a period of up to 50 h. BVdUrd was rapidly absorbed, peak plasma levels of 0.6-7.1 micrograms/ml being achieved after 1-2 h. Following a rapid decline, plasma BVdUrd levels remained higher than 10 ng/ml for up to 2 days after BVdUrd administration. The total body clearance of FUra was approximately 61/h and t1/2 markedly increased to 4-7 h. The mean urinary excretion of FUra was 50%. No differences in FUra kinetics were observed between patients receiving one or three oral doses of BVdUrd. We conclude that the concomitant use and subsequent interaction of FUra and the antiviral agent BVdUrd resulted in an impressive inhibition of FUra breakdown and marked increase of renal clearance. The findings indicate that the simultaneous use of FUra and drugs resembling this antiviral agent in patients may result in unexpected toxicity. Further experience with BVdUrd and new analogues might enable the development of new FUra treatment schedules and treatment designs e.g. combinations with leucovorin.