Since
2-fluoro-beta-alanine (
FBAL) conjugates of
bile acids (BA), the primary biliary metabolites of fluoropyrimidine (FP) drugs, have been suggested to be related to the hepatotoxicity which develops in patients receiving FP
chemotherapy by intrahepatic arterial infusion (Proc. Natl. Acad. Sci. USA 84, 5439-5443, 1987), it was important to determine whether they undergo enterohepatic circulation and hence accumulate in the liver and biliary system. In initial studies, sensitivity of
FBAL-BA conjugates to hydrolysis by pancreatic
enzymes was examined. In subsequent in vivo studies, a model
FBAL-BA conjugate,
FBAL-
chenodeoxycholate (
FBAL-CDC), was introduced into the lumen of the small intestine of anesthetized rats with
biliary fistulas to quantitate the intestinal absorption, metabolism and tissue distribution of the conjugate. The results indicated that: (1)
FBAL-BA conjugates were resistant to hydrolysis by pancreatic
enzymes (
carboxypeptidase A,
carboxypeptidase B and
trypsin) and by human pancreatic juice, but were completely hydrolyzed by cholyglycine
hydrolase. (2) At least one-half of the administered
FBAL-CDC was deconjugated during the process of intestinal absorption, as shown by HPLC analysis of the radioactivity in portal venous blood. (3) Deconjugated
FBAL or CDC was reconjugated in liver with other
bile acids or
amino acids (
glycine and
taurine), respectively, as shown by radiochromatography of bile. (4)
FBAL, formed as a result of hydrolysis of
FBAL-CDC, had a wide tissue distribution. In conclusion,
FBAL-CDC has a rapid turnover during its enterohepatic circulation due to deconjugation in the intestine and reconjugation in the liver.