Fluorouracil and the new oral fluorinated pyrimidines

OBJECTIVE: To briefly review the biotransformation and bioavailability of f luorouracil (5-FU); discuss the effects of dihydropyrimidine dehydrogenase (DpD) on the efficacy and toxicity profiles of 5-FU; and review a new class of drugs known collectively as the oral fluorinated pyrimidines, which inh ibit or circumvent DpD activity and, when administered with 5-FU, alter its pharmacokinetic and pharmacodynamic properties. DATA SOURCES: A MEDLINE literature search was conducted (1966-March 1999), using the search terms fluoropyrimidines, fluorouracil, 5-FU, fluorinated p yrimidines, capecitabine, eniluracil, uracil-tegafur, uracil-ftorafur, UR; S1, BMS-247616, and BOf-A2. Reference lists, bibliographies of pertinent ar ticles, and abstracts from the American Society of Clinical Oncology and th e San Antonio Breast Cancer Symposium annual meetings were also identified and reviewed. Both preclinical and clinical literature were reviewed and an alyzed. DATA SYNTHESIS: The new oral fluorinated pyrimidines appear to produce anti tumor activity equivalent or superior to that of intravenously administered 5-FU by achieving higher intratumoral 5-FU concentrations or sustained 5-F U exposure. These agents are generally associated with manageable and non-l ife-threatening toxicities. The oral route of administration facilitates ea se of administration and may reduce total healthcare costs associated with 5-FU-sensitive tumors. More Studies are needed to assess the therapeutic an d economic benefits of the oral fluorinated pyrimidines. CONCLUSIONS: The bioavailability, efficacy, and toxicity of 5-FU depend on its catabolic rate-limiting enzyme, DpD. The new oral fluorinated pyrimidin es inhibit or circumvent DpD activity and, when combined with 5-FU, increas e 5-FU's bioavailability and cytotoxic effects and decrease its toxicities. Results of Phase I and II studies in patients with a variety of malignanci es suggest positive outcomes, including greater efficacy, less drug-related toxicity, lower costs related to drug administration, and greater patient convenience.