Disposition and metabolism of 2-fluoro-beta-alanine conjugates of bile acids following secretion into bile.
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.
Zhang
R W
RW
Department of Pharmacology, University of Alabama, Birmingham 35294.
Barnes
S
S
Diasio
R B
RB
D000818:Animals; D001646:Bile / Q000378:metabolism*; D001647:Bile Acids and Salts / Q000378:metabolism* / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid; D007408:Intestinal Absorption; D008099:Liver / Q000378:metabolism*; D008297:Male; D008869:Microtubule-Associated Proteins / Q000302:isolation & purification*; D008954:Models, Biological; D011743:Pyrimidines / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D012636:Secretory Rate; D014580:Ursodeoxycholic Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics
D001647:Bile Acids and Salts; D008869:Microtubule-Associated Proteins; D011743:Pyrimidines; D015091:beta-Alanine; C032348:alpha-fluoro-beta-alanine; D014580:Ursodeoxycholic Acid