INVIVO F-19 NMR-SPECTROSCOPY OF THE ANTIMETABOLITE 5-FLUOROURACIL AND ITS ANALOGS - AN ASSESSMENT OF DRUG-METABOLISM

The metabolism of 5-fluorouracil (5FU) and its analogues 2'-deoxy-5-nuorouridine (2'FdURD), 5'-deoxy-5-fluorouridine (5'FdURD) and R,S-1-(tetrahydro-2-furyl)-5-fluorouracil (Ftorafur) has been studied by 19F NMR in rat liver and the rat S.G. Prolactinoma. In experiments using i.v. bolus injections of 0.46 mmol/kg 5FU was cleared more rapidly from the liver than 5'FdURD (t 1 2 of 4.7 ± 0.6 vs 15.8 ± 0.8 min, P < 0.001). Alphafluoro-beta-alanine (FBALA) production was almost identical after 5FU or 2'FdURD but slower and more sustained after 5'FdURD and still slower after Ftorafur. Both 5FU and 2'FdURD caused formation of toxic fluoronucleotides in S.G. Prolactinomas when administered i.v (0.92 mmol/kg bolus). After i.v. infusion (0.23 mmol/kg/hr for 4 hr) 5FU produced fluoronucleotides whereas 2'FdURD did not; however, both 5FU and 2'FdURD (0.19 mmol/kg daily i.p. for 7 days) suppressed tumour growth. FBALA was observed in tumors following 5FU and 2'FdURD. Infusion of FBALA itself (0.17 mmol/kg/hr/ for 4 hr i.v.) led to signal in the tumour, so this compound could have been formed in the liver. These data demonstrate that 19F NMR can monitor drug metabolism in vivo. © 1990.