This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Sweeny, D. J. Articles by Diasio, R. B. Search for Related Content PubMed PubMed Citation Articles by Sweeny, D. J. Articles by Diasio, R. B.

Formation of Conjugates of 2-Fluoro-ß-alanine and Bile Acids during the Metabolism of 5-Fluorouracil and 5-Fluoro-2-deoxyuridine in the Isolated Perfused Rat Liver¹

Division of Clinical Pharmacology, Comprehensive Cancer Center, and Department of Pharmacology, University of Alabama at Birmingham, Birmingham, Alabama 35294

We have recently demonstrated that the major biliary metabolite of 5-fluorouracil (FUra) in cancer patients is a conjugate of the FUra catabolite 2-fluoro-ß-alanine (FBAL) and cholic acid (D. J. Sweeny, S. Barnes, G. Heggie, and R. B. Diasio. Proc. Natl. Acad. Sci. USA, 84: 5439–5443, 1987). This finding prompted us to further examine the metabolism and biliary excretion of clinically relevant concentrations of the fluoropyrimidines FUra and 5-fluoro-2'-deoxyuridine (FdUrd) using the isolated perfused rat liver. During infusion of fluoropyrimidines, rates of appearance of metabolites in bile were similar with both 1 µM FUra and 1 µM FdUrd but were 9-fold higher with 25 µM FUra. Analysis by high performance liquid chromatography demonstrated that unmetabolized fluoropyrimidines and known catabolites (i.e., FBAL) accounted for less than 15% of the total metabolites in bile and that the majority of the biliary metabolites were eluted as three distinct nonpolar compounds. Fast atom bombardment-mass spectrometry demonstrated that these unique metabolites had molecular weights of 497 (peak 1), 497 (peak 2), and 481 (peak 3). These metabolites were hydrolyzed by cholylglycine hydrolase to FBAL and unconjugated bile acids that were identified by gas chromatography-mass spectrometry to be -muricholic acid (peak 1), cholic acid (peak 2), and chenodeoxycholic acid (peak 3). Thus, the major biliary metabolites of FUra and FdUrd were identified as N-(bile acid)-FBAL conjugates. While the N-(bile acid)-FBAL conjugates were the major metabolites in bile, dihydroFUra was the major (>70%) metabolite eliminated into perfusate. In summary, these results demonstrate that FUra and FdUrd undergo similar metabolism in the isolated perfused rat liver and, as was observed in humans, the major biliary fluoropyrimidine metabolites are conjugates of FBAL and bile acids.

¹ Supported by USPHS Grant CA-40530.

² To whom requests for reprints should be addressed, at P. O. Box 186, Volker Hall, University of Alabama at Birmingham, Birmingham, AL 35294.

Received 10/21/87. Revised 12/31/87. Accepted 1/20/88.