19F NMR spectrometry evidence for bile acid conjugates of alpha-fluoro-beta-alanine as the main biliary metabolites of antineoplastic fluoropyrimidines in humans

Abstract

The human biliary excretion of antineoplastic fluoropyrimidines was studied using 19F NMR. This method allows a direct detection of all the fluorinated metabolites of a fluorinated drug and requires no labeled compound. From a patient with an external bile derivation, treated with 5'-deoxy-5-fluorouridine (5'dFUrd), the biliary excretion of 5'dFUrd metabolites was low (0.8% of the injected dose) and made up of alpha-fluoro-beta-alanine (FBAL) and fluoride ion (F-) which represented approximately equal to 10% of the excreted metabolites and approximately equal to 90% of unknown metabolites. These unknown metabolites were conjugates of FBAL with the two "primary" bile acids only present in the bile of patients with an external bile drainage, i.e. cholic and chenodeoxycholic acids, in a 3:1 ratio. In the bile obtained at surgery from a patient treated with intrahepatic 5-fluorouracil, the major metabolites were conjugates of FBAL with the three major bile acids of human bile, i.e. cholic, deoxycholic, and chenodeoxycholic acids. Moreover, 19F NMR showed that only one of the two diastereoisomers of each conjugate of FBAL with bile acids was formed in vivo, confirming that metabolic FBAL is optically active.