Disposition and metabolism of 2-fluoro-β-alanine conjugates of bile acids following secretion into bile

Ruiwen Zhang, Stephen Barnes, Robert B Diasio

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Since 2-fluoro-β-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 cholylglycine hydrolase. (2) At least one-half of the administered FBAL-CDC was deconjugeted 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.

Original languageEnglish (US)
Pages (from-to)179-186
Number of pages8
JournalBBA - Molecular Basis of Disease
Volume1096
Issue number3
DOIs
StatePublished - Apr 15 1991
Externally publishedYes

Fingerprint

Bile Acids and Salts
Bile
Alanine
Chenodeoxycholic Acid
Enterohepatic Circulation
Hydrolysis
Intestinal Absorption
choloylglycine hydrolase
Tissue Distribution
Liver
Carboxypeptidase B
alpha-fluoro-beta-alanine
Biliary Fistula
Pancreatic Juice
Taurine
Biliary Tract
Enzymes
Centers for Disease Control and Prevention (U.S.)
Glycine
Trypsin

Keywords

  • 2-Fluoro-β-alanine
  • Bile acid conjugation
  • Enterohepatic circulation

ASJC Scopus subject areas

  • Biophysics
  • Molecular Biology
  • Molecular Medicine

Cite this

Disposition and metabolism of 2-fluoro-β-alanine conjugates of bile acids following secretion into bile. / Zhang, Ruiwen; Barnes, Stephen; Diasio, Robert B.

In: BBA - Molecular Basis of Disease, Vol. 1096, No. 3, 15.04.1991, p. 179-186.

Research output: Contribution to journalArticle

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abstract = "Since 2-fluoro-β-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 cholylglycine hydrolase. (2) At least one-half of the administered FBAL-CDC was deconjugeted 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.",
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