Metabolism of trifluorothymidine (TFT) and its transport across the blood-brain barrier (BBB) has been measured quantitatively in rats by fluorine-19 nuclear magnetic resonance spectroscopy ((19)F NMR). It is demonstrated that TFT crosses the BBB in micromolar quantities and is metabolized in brain tissue primarily to its free base trifluoromethyluracil (TFMU) by the enzyme thymidine phosphorylase (TP). It is further proposed that the rate of TFMU production can be used as a measure of cerebral TP. The glycols of both TFMU, and to a lesser degree TFT, are generated via an oxidative route. In contrast, the major pathway for hepatic metabolism of this compound is through reduction of the nitrogen base moiety and generation of 5-6-dihydro species followed by ring degradation. Thus, in addition to TFMU as well as the dihydroxy (glycol)-, and the dihydro-species of both TFT and TFMU, alpha-trifluoromethyl-beta-ureidopropionic acid (F(3)MUPA) and alpha-trifluoromethyl-beta-alanine (F(3)MBA) were detected in liver extracts. The total metabolite levels in liver were 2-5 times higher than in the brain. Low levels of fluoride ion were detected in all the extracts from brain and liver, as well as blood and urine. This study characterizes TFT as a potential chemotherapeutic agent for use against brain tumors.Copyright 1999 John Wiley & Sons, Ltd.
