Intestinal absorption and biliary secretion of ursodeoxycholic acid and its taurine conjugate

Rudolph, G; Kloeters-Plachky, Petra; Sauer, Pieter J. J.; Stiehl, A.

doi:10.1046/j.1365-2362.2002.01030.x

Cited by 25 publications

(18 citation statements)

References 55 publications

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“…7 The in vivo studies were confirmed by the liver slice incubations, which showed that the major metabolite of norUDCA was a glucuronide, and that little N-acyl amidation occurred. In contrast, UDCA was conjugated with glycine or taurine, in agreement with in vivo human studies 33 We explain the strong choleresis induced by norUDCA and its metabolites by two mechanisms. The first is the cholehepatic shunting of secreted norUDCA as evidenced by the enrichment of bile in bicarbonate.…”

Section: Discussionsupporting

confidence: 86%

Novel biotransformation and physiological properties of norursodeoxycholic acid in humans

et al. 2005

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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 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. (HEPATOLOGY 2005;42:1391-1398

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Section: Discussionsupporting

confidence: 86%

Novel biotransformation and physiological properties of norursodeoxycholic acid in humans

et al. 2005

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“…When administered orally, unconjugated UDCA on the first pass through the liver is rapidly conjugated with glycine or taurine. 46 After UDCA, bile was mainly enriched with the glycine conjugate of UDCA, and at very high UDCA doses this percentage increased only a little (Table 3). Several studies have suggested that the taurine conjugates may have more pronounced hepatoprotective effects than UDCA.…”

Section: Discussionmentioning

confidence: 99%

Effect of high-dose ursodeoxycholic acid on its biliary enrichment in primary sclerosing cholangitis

et al. 2004

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Ursodeoxycholic acid (UDCA) has beneficial effects in cholestatic liver diseases. In primary sclerosing cholangitis (PSC), there is evidence that high doses (؎20 mg/kg) of UDCA may be more effective than average doses. Biliary enrichment of UDCA at such high doses may represent the decisive factor for its beneficial effect. Up to now it is not clear how high-dose UDCA correlates with its biliary enrichment and whether bacterial degradation of large amounts of UDCA may lead to an increased bacterial formation of more toxic hydrophobic bile acids. We determined the biliary bile acid composition in 56 patients with PSC including 30 patients with repeat bile samples treated with various doses of UDCA. At a UDCA dose of 10 -13 mg/kg/d (n ‫؍‬ 18) biliary UDCA represented 43.1% ؉ 0.3% (mean ؉ SD) of total bile acids; at a UDCA dose of 14 -17 mg/kg (n ‫؍‬ 14), its biliary content increased to 46.9% ؉ 0.3%, at 18 -21 mg/kg (n ‫؍‬ 34) to 55.9% ؉ 0.2%, at 22-25 mg/kg (n ‫؍‬ 12) to 58.6% ؉ 2.3%, and at 26 -32 mg/kg (n ‫؍‬ 8) to 57.7% ؉ 0.4%. During UDCA treatment, the biliary content of all other bile acids was unchanged or decreased. In conclusion, biliary enrichment of UDCA increases with increasing dose and reaches a plateau at 22-25 mg/kg. There was no increase of toxic hydrophobic bile acids. If biliary enrichment of UDCA represents the decisive factor for its clinical effect, it seems likely that UDCA doses of up to 22-25 mg/kg may be more effective than lower doses. (HEPATOLOGY 2004;40:693-698.)

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“…The ob/ob mice were given TUDCA (Tokyo Tanabe, Tokyo, Japan) at a dose of 500 mg/kg twice a day (8:00 AM and 8:00 PM) by gastric gavage for 3 weeks (OB-TUDCA group, n = 6). Given that the oral bioavailability of TUDCA is approximately 65% [23], we doubled the dose of TUDCA that used in intraperitoneal injection [21]. We administered the same volume of tap water to control ob/ob mice (OB-control group, n = 6) and normal control C57BL/6J mice (N-control group, n = 6) twice a day by gastric gavage for 3 weeks.…”

Section: Methodsmentioning

confidence: 99%

“…Therefore, it remains inconclusive whether oral administration of TUDCA reveals similar effects to parenteral administration in terms of improving hepatic steatosis. Since orally administrated TUDCA is absorbed via active transport in the terminal ileum and undergoes a significant hepatic first pass effect and enterohepatic circulation [23], [24], the working mechanism of orally administrated TUDCA may be different from that of intraperitoneally injected TUDCA [21].…”

Section: Introductionmentioning

confidence: 99%

Changes in Hepatic Gene Expression upon Oral Administration of Taurine-Conjugated Ursodeoxycholic Acid in ob/ob Mice

et al. 2010

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Nonalcoholic fatty liver disease (NAFLD) is highly prevalent and associated with considerable morbidities. Unfortunately, there is no currently available drug established to treat NAFLD. It was recently reported that intraperitoneal administration of taurine-conjugated ursodeoxycholic acid (TUDCA) improved hepatic steatosis in ob/ob mice. We hereby examined the effect of oral TUDCA treatment on hepatic steatosis and associated changes in hepatic gene expression in ob/ob mice. We administered TUDCA to ob/ob mice at a dose of 500 mg/kg twice a day by gastric gavage for 3 weeks. Body weight, glucose homeostasis, endoplasmic reticulum (ER) stress, and hepatic gene expression were examined in comparison with control ob/ob mice and normal littermate C57BL/6J mice. Compared to the control ob/ob mice, TUDCA treated ob/ob mice revealed markedly reduced liver fat stained by oil red O (44.2±5.8% vs. 21.1±10.4%, P<0.05), whereas there was no difference in body weight, oral glucose tolerance, insulin sensitivity, and ER stress. Microarray analysis of hepatic gene expression demonstrated that oral TUDCA treatment mainly decreased the expression of genes involved in de novo lipogenesis among the components of lipid homeostasis. At pathway levels, oral TUDCA altered the genes regulating amino acid, carbohydrate, and drug metabolism in addition to lipid metabolism. In summary, oral TUDCA treatment decreased hepatic steatosis in ob/ob mice by cooperative regulation of multiple metabolic pathways, particularly by reducing the expression of genes known to regulate de novo lipogenesis.

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Intestinal absorption and biliary secretion of ursodeoxycholic acid and its taurine conjugate

Cited by 25 publications

References 55 publications

Novel biotransformation and physiological properties of norursodeoxycholic acid in humans

Novel biotransformation and physiological properties of norursodeoxycholic acid in humans

Effect of high-dose ursodeoxycholic acid on its biliary enrichment in primary sclerosing cholangitis

Changes in Hepatic Gene Expression upon Oral Administration of Taurine-Conjugated Ursodeoxycholic Acid in ob/ob Mice

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