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Novel biotransformation and physiological properties of norursodeoxycholic acid in humans
Author(s) -
Hofmann Alan F.,
Zakko Salam F.,
Lira Marco,
Clerici Carlo,
Hagey Lee R.,
Lambert K. Karel,
Steinbach Joseph H.,
Schteingart Claudio D.,
Olinga Peter,
Groothuis Geny M. M.
Publication year - 2005
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.20943
Subject(s) - taurine , biotransformation , chemistry , metabolite , ursodeoxycholic acid , in vivo , ex vivo , glucuronide , bile acid , biochemistry , amino acid , biology , in vitro , enzyme , microbiology and biotechnology
Experiments were performed in 2 volunteers to define the biotransformation and physiological properties of norursodeoxycholic acid (norUDCA), the C 23 (C 24 ‐nor) homolog of UDCA. To complement the in vivo studies, the biotransformation of norUDCA ex vivo using precision‐cut human liver slices was also characterized. In the human studies, both a tracer dose given intravenously and a physiological dose (7.9 mmol, 3.0 g) given orally were excreted equally in bile and urine. By chromatography and mass spectrometry, the dominant biotransformation product of norUDCA in bile and urine was the C‐23 ester glucuronide. Little N ‐acyl amidation (with glycine or taurine) occurred. The oral dose induced a sustained bicarbonate‐rich hypercholeresis, with total bile flow averaging 20 μL/kg/min, a rate extrapolating to 2 L/d. The increased bile flow was attributed to cholehepatic shunting of norUDCA as well to the lack of micelles in bile. Phospholipid and cholesterol secretion relative to bile acid secretion decreased during secretion of norUDCA and its metabolites, presumably also because of the absence of micelles in canalicular bile. When incubated with human liver slices, norUDCA was glucuronidated, whereas UDCA was conjugated with glycine or taurine. In conclusion , in humans, norUDCA is glucuronidated rather than amidated. In humans, but not animals, there is considerable renal elimination of the C‐23 ester glucuronide, the dominant metabolite. NorUDCA ingestion induces a bicarbonate‐rich hypercholeresis and evokes less phospholipid and cholesterol secretion into bile than UDCA. Molecules that undergo cholehepatic shunting should be powerful choleretics in humans. (H EPATOLOGY 2005;42:1391–1398.)