Pharmacokinetics and bioavailability of oral 5 '-deoxy-5-fluorouridine in cancer patients

Aims Oral administration of 5-fluorouracil (FUra), an important cytotoxic a gent, is limited by a wide variation in bioavailability. 5'-deoxy-5-fluorou ridine (dFUrd), a masked form of FUra, has shown promise clinically when gi ven intravenously or orally as a solution or tablet. This study investigate s the efficacy of an oral capsule formulation of dFUrd in generating contin uous systemic levels of this compound in cancer patients. Methods Six patients with advanced intestinal or ovarian malignancies were given three cycles of dFUrd, days 1-5, at intervals of 4 weeks. The doses o f dFUrd were 600 mg m(-2) three times daily, 800 mg m(-2) three times daily , and 1000 mg m(-2) three times daily, on cycles one, two and three, respec tively (total dose 36 g m(-2)). The initial dose in each cycle was given as a slow intravenous injection over 10 min, and the remainder orally. Plasma and urine levels of dFUrd and two of its metabolites, FUra and 5,6-dihydro -5-fluorouracil (FUraH(2)), were monitored in six patients at each dose lev el. Results AU six patients completed the study, receiving three different dose s over a 3 month period, following which one had achieved a partial respons e, one had stable disease, and four had developed progressive disease. Side -effects were negligible, and only two instances of transient diarrhoea WHO grade 1 were seen. Total body clearance (CLtot) of intravenous dFUrd decre ased with increasing dose; 2.7, 2.0 and 1.3 1 min(-1) m(-2), following dose s of 600, 800 and 1000 mg m(-2) respectively. The mean elimination half-lif e of intravenous dFUrd increased with the dose from 15 to 22 min. Oral dFUr d was rapidly absorbed with a lag time of less than 20 min. The mean elimin ation half-life (t(1/2, z)) Of Oral dFUrd was 32-45 min in the dose range 6 00-1000 mg m(-2) The AUC of FUra and FUraH(2) increased overproportionally with increasing intravenous doses of dFUrd. The mean systemic bioavailabili ty of oral dFUrd was 34-47%. Conclusions dFUrd, which selectively releases the antimetabolite FUra in tu mour cells, can be,given orally at doses of 600-1000 mg m(-2) three times d aily for 5 days. The systemic levels achieved are equivalent to those seen following continuous infusions of dFUrd or FUra. Toxicity is tolerable, and further clinical investigation of oral dFUrd is warranted.