Quantitative F-19 NMR study of trifluorothymidine metabolism in rat brain

Metabolism of trifluorothymidine (TFT) and its transport across the blood-b rain barrier (BBB) has been measured quantitatively in rats by fluorine-19 nuclear magnetic resonance spectroscopy (F-19 NMR). It is demonstrated that TFT crosses the BBB in micromolar quantities and is metabolized in brain t issue 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 TF MU, and to a lesser degree TFT, are generated via an oxidative route. In co ntrast, the major pathway for hepatic metabolism of this compound is throug h reduction of the nitrogen base moiety and generation of 5-6-dihydro speci es followed by ring degradation. Thus, in addition to TFMU as well as the d ihydroxy (glycol)-, and the dihydro-species of both TFT and TFMU, alpha-tri fluoromethyl-beta-ureidopropionic acid (F(3)MUPA) and alpha-trifluoromethyl -beta-alanine (F(3)MBA) were detected in liver extracts. The total metaboli te levels in Liver were 2-5 times higher than in the brain. Low levels of f luoride ion were detected in all the extracts from brain and liver, as well as blood and urine. This study characterizes TFT as a potential chemothera peutic agent for use against brain tumors. Copyright (C) 1999 John Wiley & Sons, Ltd.