5-Ethynyluracil (776C85): a potent modulator of the pharmacokinetics and antitumor efficacy of 5-fluorouracil.
5-Ethynyluracil (5-EU, 776C85) is a mechanism-based irreversible inhibitor of dihydropyrimidine dehydrogenase (EC 1.3.1.2), the rate-determining 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 and 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 plasma concentration-time curve of 5-FU. 5-FU oral bioavailability was approximately 100% in rats pretreated with 5-EU. Consequently, 5-EU induced a linear relationship between the area under the plasma concentration-time curve and the oral dose of 5-FU. As expected from the preservation of plasma 5-FU, 5-EU potentiated the antitumor activity and the 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 and thereby increased the therapeutic index of 5-FU 2- to 4-fold.
Baccanari
D P
DP
Division of Molecular Genetics and Microbiology, Burroughs Wellcome Co, Research Triangle Park, NC 27709.
Davis
S T
ST
Knick
V C
VC
Spector
T
T
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D003110:Colonic Neoplasms / Q000188:drug therapy; D042943:Dihydrouracil Dehydrogenase (NADP); D004357:Drug Synergism; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D009374:Neoplasms, Experimental / Q000188:drug therapy; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D010954:Plasmacytoma / Q000188:drug therapy; D051381:Rats; D013810:Therapeutic Equivalency; D014498:Uracil / Q000008:administration & dosage / Q000031:analogs & derivatives*
C073482:eniluracil; D014498:Uracil; D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil