776C85 is a potent inactivator of dihydropyrimidine dehydrogenase (DPD, enzyme catalogue 1.3.1.2), the first enzyme in the degradative pathway of 5-fluorouracil (5-FU). In preclinical studies, doses of 776C85 sufficient to inactivate greater than 99% of DPD were non-toxic and exhibited no antiproliferative activity in mice and rats. Pretreatment with 776C85 significantly increased the bioavailability and reduced the pharmacokinetic variability of oral 5-FU in aminal models. These studies also demonstrated that 776C85 changed the route of 5-FU elimination, from degradation by DPD in the liver and extrahepatic tissues to renal elimination of the unchanged parent compound. 776C85 also increased the antitumor efficacy of 5-FU and increased the therapeutic index of 5-FU by up to six-fold in three rodent tumor models. Preliminary results from Phase I studies demonstrate that 776C85 increases the half-life of 5-FU from approximately 20 minutes to 4.5 hours. Analysis of 5-FU concentrations in the patient's urine showed that only 50 to 70% of the 5-FU dose could be accounted for by renal elimination. This study is designed to determine the effects of 776C85 on the elimination of orally and intravenously administered 5-FU, with an emphasis on the determination of any non-renal route of elimination.
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