Studies on the Fate of 5-Fluoro-1, 3-bis (tetrahydro-2-furanyl)-2, 4-pyrimidinedione (FD-1), a New Antitumor Agent. I. Absorption, Distribution, Excretion and Metabolism of FD-1 administered orally to Rats

• Published in: YAKUGAKU ZASSHI Vol. 98; no. 4; pp. 525 - 536
• Main Authors: KAWAGUCHI, YASURO, NAKAMURA, YOSHIMASA, SATO, TOSHIYUKI, TAKEDA, SETSUO, MARUNAKA, TERUYOSHI, FUJII, SETSURO
• Format: Journal Article
• Language: English; Japanese
• Published: Japan The Pharmaceutical Society of Japan 01-04-1978
• Subjects: 5-fluoro-1, 3-bis (tetrahydro-2-furanyl)-2, 4-pyrimidinedione; 5-fluoro-1-(tetrahydro-2-furanyl)-2, 4-pyrimidinedione; 5-fluoro-3-(tetrahydro-2-furanyl)-2, 4-pyrimidinedione; Absorption; Administration, Oral; Animals; Antineoplastic Agents - metabolism; antitumor agent; drug metabolism; Furans - metabolism; gas chromatography-mass spectrometry; Male; microsomal drug-metabolizing enzyme; Pyrimidinones - metabolism; Rats; thin-layer chromatography; Time Factors; Tissue Distribution; γ-hydroxybutyric acid
• ISSN: 0031-6903; 1347-5231
• DOI: 10.1248/yakushi1947.98.4_525

After oral administration of 5-fluoro-1, 3-bis (tetrahydro-2-furanyl)-2, 4-pyrimidinedione (FD-1), the level of 5-fluoro-2, 4-pyrimidinedione (5-FU) was 5 to 7 times higher in the plasma and normal tissues and 8 to 12 times in tumor tissue than after administration of 5-fluoro-1-(tetrahydro-2-furanyl)-2, 4-pyrimidinedione (FT). Moreover, these levels were maintained longer than after administration of FT. In tumor tissue, the concentration of 5-FU was still as high as 1.42 μg/g 12 hr after administration of FD-1. FD-1 was degraded to 5-fluoro-3-(tetrahydro-2-furanyl)-2, 4-pyrimidinedione (3-FT) by liver microsomal drug-metabolizing enzymes in vitro and to FT spontaneously. Subsequently, FT was converted enzymically to the active substance, 5-FU, and 3-FT changed to 5-FU spontaneously. Conversion of FD-1 to 5-FU via 3-FT was greater than via FT. It is concluded that a large amount of 5-FU formed after administration of FD-1 is formed via 3-FT. γ-Hydroxybutyric acid was found to be formed in vivo and in vitro from the tetrahydrofuranyl group of FD-1.