Novel biotransformation and physiological properties of norursodeoxycholic acid in humans
| Autor: | Joseph H. Steinbach, Geny M. M. Groothuis, Salam F. Zakko, Alan F. Hofmann, Carlo Clerici, K. Karel Lambert, Marco Lira, Claudio D. Schteingart, Peter Olinga, Lee R. Hagey |
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| Přispěvatelé: | Groningen University Institute for Drug Exploration (GUIDE), Nanomedicine & Drug Targeting, Biopharmaceuticals, Discovery, Design and Delivery (BDDD), Groningen Institute for Organ Transplantation (GIOT) |
| Jazyk: | angličtina |
| Rok vydání: | 2005 |
| Předmět: |
Male
medicine.medical_specialty Taurine Metabolite FLOW Phospholipid INTESTINAL-ABSORPTION CHROMATOGRAPHY METABOLISM Intestinal absorption chemistry.chemical_compound Internal medicine medicine Humans Biotransformation Phospholipids Aged Hepatology Cholesterol Metabolism Middle Aged UNCONJUGATED BILE-ACIDS Ursodeoxycholic acid URSODEOXYCHOLIC ACID Endocrinology HEPATIC TRANSPORT chemistry Liver BILIARY LIPID SECRETION RAT Norsteroids Glucuronide SIDE-CHAIN medicine.drug |
| Zdroj: | Hepatology, 42(6), 1391-1398. Wiley |
| ISSN: | 0270-9139 |
| Popis: | 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 mu L/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 bicarbonaterich hypercholeresis and evokes less phospholipid and cholesterol secretion into bile than UDCA. Molecules that undergo cholehepatic shunting should be powerful choleretics in humans. |
| Databáze: | OpenAIRE |
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