5-ETHYNYLURACIL (776C85) - EFFECTS ON THE ANTITUMOR-ACTIVITY AND PHARMACOKINETICS OF TEGAFUR, A PRODRUG OF 5-FLUOROURACIL

We studied the effects of 5-ethynyluracil (776C85 and 776C), a potent mechanism-based inactivator of dihydropyrimidine dehydrogenase, on the antitumor efficacy and pharmacokinetics of tegafur (FT), a prodrug of 5-fluorouracil (5-FU), in rats with large s.c. colon carcinoma, Rats were dosed p.o. once daily for 7 days with either FT, FT and uracil in a 1:4 molar ratio (UFT), FT 1 h after 776C (776C/PT), or UFT 1 h afte r 776C (776C/UFT), 776C, which was dosed at 1 mg/kg, had neither intri nsic antitumor activity nor toxicity, The rank order in antitumor effi cacy at the maximal tolerated dose of the FT (mg/kg/day) component was 776C/FT (5 mg/kg/day) greater than or equal to UFT (80 mg/kg/day) = 7 76C/UFT (5 mg/kg/ day) much greater than FT (200 mg/kg/day). One-hundr ed % of rats treated with 776C/FT had complete and sustained tumor reg ression with no severe toxicity. The area under the plasma 5-FU concen tration versus the time curve generated from UFT, FT, and 776C/FT at t heir maximum tolerated dose was 140, 50, and 27 mu M . h, respectively . The area under the concentration in plasma versus time curve did not correlate with the rank order of antitumor efficacy, The vast majorit y of 5-FU derived from FT (alone) appeared to be rapidly catabolized, Furthermore, plasma exposure of 5-FU derived from UFT was more variabl e than that from 776C/FT. Each therapy also produced different levels of plasma uracil, Endogenous plasma uracil levels (1-3 mu M) were not affected by FT but increased to 100 mu M after dosing with 776C, Plasm a uracil from UFT was 800 mu M 1 h after dosing, These results suggest that moderately elevated uracil (776C/FT) may be beneficial, whereas uracil that is greatly elevated during the first 5 h (UFT) and 5-FU ca tabolites (FT alone) may interfere with antitumor efficacy, 776C, coad ministered with FT, could provide once-a-day oral therapy for cancer p atients.