5-ETHYNYLURACIL (776C85) - A POTENT MODULATOR OF THE PHARMACOKINETICSAND ANTITUMOR EFFICACY OF 5-FLUOROURACIL

5-Ethynyluracil (5-EU, 776C85) is a mechanism-based irreversible inhib itor of dihydropyrimidine dehydrogenase (EC 1.3.1.2), the rate-determi ning enzyme in 5-fluorouracil (5-FU) catabolism. In the present study, 5-EU was found to be a potent modulator of 5-FU catabolism in mice an d rats. Liver extracts prepared up to 6 hr after a 5-EU dose (2 mg/kg) were >96% inhibited in their ability to catalyze 5-FU degradation. 5- EU treatment increased the elimination t1/2 and the area under the pla sma concentration-time curve of 5-FU. 5-FU oral bioavailability was al most-equal-to 100% in rats pretreated with 5-EU. Consequently, 5-EU in duced a linear relationship between the area under the plasma concentr ation-time curve and the oral dose of 5-FU. As expected from the prese rvation of plasma 5-FU, 5-EU potentiated the antitumor activity and th e toxicity of 5-FU in two mouse tumor models (Colon 38 and MOPC-315). However, 5-EU potentiated the antitumor activity to a greater degree a nd thereby increased the therapeutic index of 5-FU 2- to 4-fold.