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In Vivo Effect of 5-Ethynyluracil on 5-Fluorouracil Metabolism Determined by ¹⁹F Nuclear Magnetic Resonance Spectroscopy

Yale University School of Medicine, Department of Internal Medicine, Section of Medical Oncology, New Haven, Connecticut 06520 [E. R. A., J. J. L., D. J. C., G. P.], and Glaxo Wellcome, Research Triangle Park, North Carolina 27709 [T. S.]

Biochemical modulation of 5-fluorouracil (5-FU) has been used over the past 20 years to improve the therapeutic efficacy of this antineoplastic agent. Recently, modulation of the catabolic pathway of this fluoropy-rimidine has been the focus of extensive preclinical and clinical investigation. Dihydropyrimidine dehydrogenase catalyzes the rate-limiting step in the catabolism of 5-FU and rapidly degrades 60–90% of the drug. An irreversible inactivating inhibitor of this enzyme, 5-ethynyluracil (EU), markedly improves the antitumor effect of 5-FU in animal models. Early clinical studies have shown a substantial alteration of the systemic disposition of 5-FU with an increase in 5-FU terminal half-life and have also indicated that EU allows safe oral administration of 5-FU by improving the oral bioavailability of the fluoropyrimidine, which is otherwise too erratic and unpredictable for a drug with such a limited therapeutic window.

We evaluated the effect of EU on the metabolism of 5-FU in mice bearing colon 38 tumors using ¹⁹F nuclear magnetic resonance spectroscopy. Ex vivo measurements of tissue extracts from liver, kidney, and tumor indicated a >95% elimination of -fluoro-ß-ureidopropionic acid and -fluoro-ß-alanine signals in the tissues of mice that received 2 mg/kg of EU before administration of 5-FU. The spectra also showed an increased formation of fluoronucleotides in both normal and tumor tissues, a prolonged presence of 5-FU, and the accumulation of 5-fluorouridine that otherwise is undetectable, particularly in normal tissues. The in vivo NMR experiments on colon 38 tumors confirmed these findings, showing a complete elimination of the -fluoro-ß-ureidopropionic acid and -fluoro-ß-alanine signals in tumors treated with EU and a dramatic formation and accumulation of 5-fluorouridine mono-, di-, and triphosphates and 5-fluorouridine. Thus, by inactivating dihydropyrimidine dehydrogenase, EU prolonged the half-life for 5-FU, almost completely eliminated its catabolism for 4–6 h, which led to an increased accumulation of 5-fluorouridine mono-, di-, and triphosphates in both normal and tumor tissues.

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