Fluorouracil and the new oral fluorinated pyrimidines

• Published in: The Annals of pharmacotherapy 2001-02, Vol.35 (2), p.217-227
• Main Author: Kuhn, JG
• Format: Article
• Language: English
• Subjects: Animals; Antimetabolites, Antineoplastic - pharmacokinetics; Antimetabolites, Antineoplastic - therapeutic use; Antineoplastic agents; Biological and medical sciences; Biological Availability; Biotransformation; Chemotherapy; Fluorouracil - pharmacokinetics; Fluorouracil - therapeutic use; Humans; Medical sciences; Neoplasms - drug therapy; Pharmacology. Drug treatments; Pyrimidines - pharmacokinetics
• ISSN: 1060-0280; 1542-6270
• DOI: 10.1345/aph.10096

OBJECTIVE: To briefly review the biotransformation and bioavailability of fluorouracil (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 inhibit 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 pyrimidines, capecitabine, eniluracil, uraciltegafur, uracilftorafur, UFT, S1, BMS-247616, and BOF-A2. Reference lists, bibliographies of pertinent articles, and abstracts from the American Society of Clinical Oncology and the San Antonio Breast Cancer Symposium annual meetings were also identified and reviewed. Both preclinical and clinical literature were reviewed and analyzed. DATA SYNTHESIS: The new oral fluorinated pyrimidines appear to produce antitumor activity equivalent or superior to that of intravenously administered 5-FU by achieving higher intratumoral 5-FU concentrations or sustained 5-FU exposure. These agents are generally associated with manageable and non-life—threatening toxicities. The oral route of administration facilitates ease of administration and may reduce total healthcare costs associated with 5-FU—sensitive tumors. More studies are needed to assess the therapeutic and 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 pyrimidines inhibit or circumvent DpD activity and, when combined with 5-FU, increase 5-FU's bioavailability and cytotoxic effects and decrease its toxicities. Results of Phase I and II studies in patients with a variety of malignancies suggest positive outcomes, including greater efficacy, less drug-related toxicity, lower costs related to drug administration, and greater patient convenience.