Chronic Administration Of Ursodeoxycholic Acid Research Articles

Long-Term Ursodeoxycholic Acid Therapy Does Not Alter Lithocholic Acid Levels in Patients with Cystic Fibrosis with Associated Liver Disease

To evaluate the fasting and postprandial serum bile acid composition in patients with cystic fibrosis-associated liver disease (CFLD) after chronic administration of ursodeoxycholic acid (UDCA) (20mg/kg/day). The aim was to specifically focus on the extent of biotransformation of UDCA to its hepatotoxic metabolite, lithocholic acid, because of recent concerns regarding the safety of long-term, high-dose UDCA treatment for CFLD. Twenty patients with CFLD (median age 16years, range: 2.4-35.0) prescribed UDCA therapy for at least 2years were studied. Total and individual serum bile acids were measured by stable-isotope dilution mass spectrometry, in fasting and 2-hour postprandial samples taken during chronic UDCA (20mg/kg/day) administration. During chronic UDCA administration (median duration 8years, IQR: 6-16), UDCA became the predominant serum bile acid in all patients (median, IQR: 3.17, 1.25-5.56μmol/L) and chenodeoxycholic acid concentrations were greater than cholic acid (1.86, 1.00-4.70μmol/L vs 0.40, 0.24-2.71μmol/L). The secondary bile acids, deoxycholate and lithocholate, were present in very low concentrations in fasted serum (<0.05μmol/L). After UDCA administration, 2-hour postprandial concentrations of both UDCA and chenodeoxycholic acid significantly increased (P<.01), but no significant changes in serum lithocholic acid concentrations were observed. These data do not support recent suggestions that enhanced biotransformation of UDCA to the hepatotoxic secondary bile acid lithocholic occurs when patients with CFLD are treated with relatively high doses of UDCA.

The Role of Lipophilic Bile Acids in the Development of Cirrhotic Cardiomyopathy

Marked hemodynamic changes occur in humans and experimental animals with cirrhotic liver disease. In the heart, basal contractility, responsiveness to beta-adrenoceptor activation, and excitation-contraction coupling (ECC) are negatively affected in models of cirrhosis and portal hypertension with portosystemic shunting (PVS), and comprise what has been called cirrhotic cardiomyopathy. These effects are accompanied by elevated circulating levels of bile acids. We investigated whether elevated bile acids act as a myocardial toxicant by exposing cardiac muscle in vitro to bile acids and compared these results with two models of cirrhotic cardiomyopathy with elevated bile acids: CCl4-induced cirrhosis and PVS. Cholic acid, a lipophilic bile acid, produced a decrease in basal cardiac contractility and responsiveness to beta-adrenoceptor activation, both of which appeared to result from altered ECC. beta-Adrenoceptor density and signaling were unaffected. Acutely, ursodeoxycholic acid, a more hydrophilic bile acid, had no effect. Cirrhosis produced a decrease in basal force, depressed beta-adrenoceptor responsiveness, and altered ECC similar to cholic acid. However, cirrhosis also altered beta-adrenoceptor signaling including decreases in cyclic AMP formation, expression of the stimulatory G protein, GS, and beta-adrenoceptor density. Displacement of lipophilic bile acids by chronic administration of ursodeoxycholic acid to rats during the development of cirrhotic cardiomyopathy produced by PVS produced attenuation of the effect on ECC. These results suggest a possible role for lipophilic bile acids in some, but not all of the myocardial consequences of chronic portal vein stenosis and CCl4-induced cirrhosis.

A missense mutation in ABCB4 gene involved in progressive familial intrahepatic cholestasis type 3 leads to a folding defect that can be rescued by low temperature #

Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a rare liver disease characterized by early onset of cholestasis that leads to cirrhosis and liver failure before adulthood. PFIC3 may be improved by chronic administration of ursodeoxycholic acid, although in many cases liver transplantation is the only therapy. The disease is caused by mutations of the adenosine triphosphate (ATP)-binding cassette, sub-family B, member 4 (ABCB4) [multidrug resistance 3 (MDR3)] gene encoding a specific hepatocellular canalicular transporter involved in biliary phosphatidylcholine secretion. Several mutations have been reported; however, the effect of individual mutations has not been investigated. ABCB4 is highly homologous to ATP-binding cassette, sub-family B, member 1 (ABCB1) (MDR1), the multidrug transporter responsible for drug resistance of cancer cells. We have studied the effect of mutation I541F localized to the first nucleotide-binding domain, which is highly conserved between ABCB4 and ABCB1. Plasmids encoding the wild-type human ABCB4 or rat ABCB1-green fluorescing protein (GFP) construct, and corresponding I541F-mutants, were expressed in hepatocellular carcinoma, human (HepG2) and Madin-Darby canine kidney (MDCK) cells. Expression studies showed that ABCB4 was localized at the bile canalicular membrane in HepG2 cells and at the apical surface in MDCK cells, whereas the I541F mutant was intracellular. In MDCK cells, ABCB1-I541F also accumulated intracellularly in compartments, which were identified as the endoplasmic reticulum and cis-Golgi, and remained partially endoH-sensitive. After shifting cells to 27 degrees C, ABCB1-I541F was expressed at the apical cell surface in a mature and active form. Similarly, ABCB4 was significantly trafficked to the membrane of bile canaliculi in HepG2 cells. Mutation I541F causes mislocalization of both ABCB4 and ABCB1. Intracellular retention of ABCB4-I541F can explain the disease in PFIC3 patients bearing this mutation. The observation that plasma membrane expression and activity can be rescued by low temperature opens perspectives to develop novel therapies for the treatment of PFIC3.

Chronic administration of ursodeoxycholic acid decreases portal pressure in rats with biliary cirrhosis

Liver cirrhosis is characterized by increased IHR (intrahepatic resistance) and lipid peroxidation, and decreased antioxidative defence. The present study investigates the effects of administration for 1 month of the antioxidant UDCA (ursodeoxycholic acid) in BDL (bile-duct-ligated) cirrhotic rats. Splanchnic haemodynamics, IHR, hepatic levels of TBARS (thiobarbituric acid-reacting substances), GSH (glutathione), SOD (superoxide dismutase) activity, nitrite, PIIINP (N-terminal propeptide of type III procollagen) and collagen deposition, histological examination of liver, mRNA expression of PIIIP-alpha1 (type III procollagen) and TGF-beta1 (transforming growth factor-beta1), protein expression of TXS (thromboxane synthase) and iNOS (inducible NO synthase), and TXA2 (thromboxane A2) production in liver perfusates were measured. The results showed that portal pressure and IHR, hepatic levels of PIIINP, hepatic collagen deposition, mRNA expression of PIIIP-alpha1 and TGF-beta1, protein expression of iNOS and TXS, and production of TXA2 in liver perfusates were significantly decreased in UDCA-treated BDL rats. The increased levels of hepatic GSH and SOD activity and decreased levels of TBARS and nitrite were also observed in UDCA-treated BDL rats. In UDCA-treated BDL rats, the reduction in portal pressure resulted from a decrease in IHR, which mostly acted through the suppression of hepatic TXA2 production and lipid peroxidation, and an increase in antioxidative defence, leading to the prevention of hepatic fibrosis.

291 Effect of chronic administration of ursodeoxycholic acid on a gastrointestinal motility in gallstones and healthy controls

291 Effect of chronic administration of ursodeoxycholic acid on a gastrointestinal motility in gallstones and healthy controls

Pharmacology of ursodeoxycholic acid, an enterohepatic drug.

The pharmacokinetics, metabolism, as well as the pharmacodynamic actions of ursodeoxycholic acid are reviewed and related to its physicochemical properties. Ursodeoxycholic acid is absorbed incompletely because of its low aqueous solubility. After absorption, it is conjugated with glycine or taurine and circulates with the endogenous bile acids. At usual doses (8-10 mg/kg/day), the pool of ursodeoxycholyl conjugates constitutes 30-60% of circulating bile acids. Ursodeoxycholic acid is metabolized by intestinal bacteriae to lithocholic acid which does not accumulate in the circulating bile acids because of efficient hepatic sulfation. Administration of ursodeoxycholic acid causes decreased cholesterol absorption, increased bile acid biosynthesis, and decreased biliary cholesterol secretion. Ursodeoxycholic acid is a choleretic agent, as all bile acids, but differs from other dihydroxy-bile acids in being non-cytotoxic because it has less affinity for membranes, and when present at micellar concentrations does not solubilize membranes. Chronic administration of ursodeoxycholic acid appears to increase canalicular transport.

Ursodeoxycholic acid improves ethinyl estradiol-induced cholestasis in the rat.

The effect of oral chronic administration of ursodeoxycholic acid has been examined in rats with cholestasis induced by ethinyl estradiol. Ursodeoxycholic acid at the dose of 25 mg kg-1 per day during 4 days, did not improve the decrease in basal bile flow and bile acid secretion induced by ethinyl estradiol alone. In contrast, when ursodeoxycholic acid was given at the same dose during 10 days, basal bile flow was significantly improved and basal bile acid secretion was restored to control values. When ursodeoxycholic acid was given at the dose of 500 mg kg-1 per day, basal bile flow and bile acid output were not further improved. However, bile flow and bile acid output under taurocholate infusion were restored to control values. Bile of rats treated with ursodeoxycholic acid was enriched with this bile acid. These results show a significant improvement of ethinyl estradiol-induced cholestasis in rats after chronic administration of ursodeoxycholic acid and support the use of this bile acid in intrahepatic cholestasis in man.

Ursodeoxycholic acid limits liver histologic alterations and portal hypertension induced by bile duct ligation in the rat

Chronic administration of ursodeoxycholic acid (UDCA) has recently been suggested as a potential treatment for cholestatic liver disease. The purpose of this study was to examine the effects of chronic oral administration of UDCA on the histological, biochemical, and hemodynamic abnormalities induced by bile duct ligation in the rat. Fifty-one rats with ligation-section of the common bile duct were randomly and blindly assigned to receive UDCA (25 mg/kg each day) or placebo by gavage for 4 weeks. At the end of the treatment period, morphometric analysis showed that in rats treated with UDCA, hepatocyte and sinusoidal volume fractions were significantly higher than in rats receiving placebo [41.9 ± 3.2% vs. 28.1 ± 1.8%, (mean ± SE) and 7.4 ± 0.1% vs. 4.3 ± 0.3%, respectively], whereas bile duct volume fraction (reflecting bile ductular proliferation) and connective tissue fraction were significantly lower in rats treated with UDCA than in rats receiving placebo (14,2 ± 1.5% vs. 20.0 ± 1.0% and 35.4 ± 2.4% vs. 47.6 ± 1.7%, respectively). Serum aminotransferase and alkaline phosphatase activities, and total serum bile acids and individual bile acid concentrations were not significantly different between the two groups. Portal pressure (12.7 ± 0.5 mm Hg vs. 17.1 ± 0.5 mm Hg), portal tributary blood flow (5.7 ± 0.4 vs. 9.3 ± 0.4 mL · min−1 · 100 g−1 body weight), and cardiac index (41.1 ± 1.8 vs. 50.6 ± 1.4 mL · min−1 · 100 g−1 body weight) were significantly lower in UDCA-treated rats than in placebo-treated animals. In portal vein stenosed rats, chronic administration of UDCA had no hemodynamic effects, a finding that suggests UDCA has no direct vasoactive effect on splanchnic circulation. It is concluded that in rats with bile duct ligation UDCA limits the severity of liver disease and consequently of portal hypertension and hyperkinetic circulation.

Effect of chronic administration of ursodeoxycholic acid on the ileal absorption of endogenous bile acids in man

The effect of long-term administration of ursodeoxycholic acid on the ileal absorption of endogenous bile acids was determined using the tauro 23 (75Se) selena-25 homotaurocholic acid test in a controlled double-blind study involving healthy subjects (n = 15). Subjects received placebo or 13 to 15 mg/kg/day ursodeoxycholic acid for 5 wk. In the placebo group (n = 7) there was no change in the composition of serum bile acids or in the mean percentage of retention of tauro 23(75Se) selena-25 homotaurocholic acid (36.1% +/- 6.0% vs. 38.7% +/- 6.7%). In contrast, in the ursodeoxycholic acid group, serum ursodeoxycholic acid conjugates increased and the percentage of retention of tauro 23 (75Se) selena-25 homotaurocholic acid fell from 45.8% +/- 6.8% to 20.5% +/- 5.7% (p less than 0.01). We conclude that ursodeoxycholic acid administration reduces ileal absorption of endogenous bile acids. These findings provide a rational explanation for the changes in the composition of the bile acid pool during ursodeoxycholic acid therapy and could have important therapeutic implications.

Effect of Ursodeoxycholic Acid (UDCA) on Pancreatic Enzyme Secretion and Gallbladder Emptying

We have used a duodenal perfusion technique to study the effect of chronic administration of ursodeoxycholic acid (UDCA) on postprandial pancreatic enzyme secretion and gallbladder emptying. Duodenal output and hepatic secretion rate of bile acid were also measured. Six gallstone subjects were studied during an evening meal and an overnight fast before and during UDCA administration (675 mg/day for 6 weeks). During the first postprandial hour, the duodenal trypsin output was reduced from 253 to 164 IU/kg/h (p less than 0.05), and mean gallbladder ejection fraction from 38 to 20% (p less than 0.05). The peak response to the meal was delayed from 30 to 50 min for trypsin output (NS) and from 25 to 45 min for gallbladder ejection fraction (p less than 0.05). Area under the curve during the first postprandial hour was decreased for trypsin output from 225 to 119 IU/kg (p less than 0.025), and for gallbladder ejection fraction from 43 to 19% (NS); but areas for the second postprandial hour were increased, so that total values were unchanged. We conclude that the pattern of response for both end organs during chronic UDCA is better described as an attenuated response to food, rather than as a simple reduction in response; and that, since the effects were unaccompanied by any quantitative changes in hepatic bile acid secretion rate, they were probably mediated via the qualitative change in biliary bile acid composition known to accompany chronic UDCA administration.

Hepatic Expression of Class I and Class Ii Major Histocompatibility Complex Molecules in Primary Biliary Cirrhosis: Effect of Ursodeoxycholic Acid

Aberrant hepatic expression of HLA molecules has been shown to be present in primary biliary cirrhosis and may play a determining role in the pathogenesis of the disease. We have studied the effect of the long-term administration of ursodeoxycholic acid on hepatic HLA expression. Nine untreated patients with primary biliary cirrhosis, eight patients treated for at least a year with ursodeoxycholic acid and eight control subjects without hepatobiliary disease were compared. HLA expression was studied on liver biopsy sections using a direct immunofluorescence technique with specific monoclonal antibodies directed against class I or class II HLA molecules. Aberrant biliary HLA class II expression was not modified by chronic administration of ursodeoxycholic acid. In contrast, aberrant hepatocyte HLA class I expression was markedly reduced. Reduction in HLA class I expression may lead to decreased cytotoxic T cell-dependent lobular necrosis, which is thought to contribute to the progression of primary biliary cirrhosis to advanced stages. These findings suggest that the beneficial effect of ursodeoxycholic acid treatment in primary biliary cirrhosis could result not only from a reduction in the intrahepatic accumulation of cytotoxic bile acids but also from a reduction in immunological injury.

Effect of chronic administration of ursodeoxycholic acid on the ileal absorption of endogenous bile acids in man

The effect of long-term administration of ursodeoxycholic acid on the ileal absorption of endogenous bile acids was determined using the tauro 23 (75Se) selena-25 homotaurocholic acid test in a controlled double-blind study involving healthy subjects (n = 15). Subjects received placebo or 13 to 15 mg/kg/day ursodeoxycholic acid for 5 wk. In the placebo group (n = 7) there was no change in the composition of serum bile acids or in the mean percentage of retention of tauro 23(75Se) selena-25 homotaurocholic acid (36.1% +/- 6.0% vs. 38.7% +/- 6.7%). In contrast, in the ursodeoxycholic acid group, serum ursodeoxycholic acid conjugates increased and the percentage of retention of tauro 23 (75Se) selena-25 homotaurocholic acid fell from 45.8% +/- 6.8% to 20.5% +/- 5.7% (p less than 0.01). We conclude that ursodeoxycholic acid administration reduces ileal absorption of endogenous bile acids. These findings provide a rational explanation for the changes in the composition of the bile acid pool during ursodeoxycholic acid therapy and could have important therapeutic implications.

Effect of ursodeoxycholic acid on biliary lipid coupling and on cholesterol absorption during fasting and eating in subjects with cholesterol gallstones

The aim of this study was to determine the effect of chronic ursodeoxycholic acid administration on coupling of bile acids with cholesterol and phospholipid in hepatic bile, and on cholesterol absorption in the duodenum. A range of bile acid secretion rates was obtained during an evening meal and an overnight fast. Duodenal perfusion of polyethylene glycol as a nonabsorbable recovery marker and of [3H]cholesterol and [14C]lecithin as absorbable recovery markers was combined with continuous intravenous infusion of indocyanine green as a hepatic bile marker. Six subjects with gallstones were studied before and during chronic administration of ursodeoxycholic acid (675 mg/day). Duplicate pretreatment studies revealed good reproducibility for biliary lipid coupling and cholesterol absorption. During ursodeoxycholic acid administration there was a significant alteration not only in bile acid/ cholesterol coupling (p < 0.001), but also in bile acid/phospholipid coupling (p < 0.001). Mean cholesterol absorption decreased from 25% to 15% (p < 0.001) during ursodeoxycholic acid administration. These effects of chronic ursodeoxycholic acid administration on biliary lipid coupling are similar to those reported for acute administration, and are thus consistent with an effect caused by bile acid lipid-solubilizing capacity.

Ileal bile salt transport: mutual inhibition in an in vivo system.

ARTICLESIleal bile salt transport: mutual inhibition in an in vivo systemKW Heaton, and L LackKW Heaton, and L LackPublished Online:01 Mar 1968https://doi.org/10.1152/ajplegacy.1968.214.3.585MoreSectionsPDF (2 MB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat Previous Back to Top Next Download PDF FiguresReferencesRelatedInformation Cited ByDrug Transport and Membrane Transport Proteins15 September 2010Membrane Transport Proteins and Drug Transport15 January 2003Modeling of active transport systemsAdvanced Drug Delivery Reviews, Vol. 54, No. 3STRUCTURAL BIOLOGY AND FUNCTION OF SOLUTE TRANSPORTERS: IMPLICATIONS FOR IDENTIFYING AND DESIGNING SUBSTRATES27 November 2002 | Drug Metabolism Reviews, Vol. 34, No. 4Effect of Chronic Administration of Tauro-hyodeoxycholic Acid on Biliary Bile Acid Composition and on Biliary Lipid Secretion in Humans8 July 2009 | Scandinavian Journal of Gastroenterology, Vol. 36, No. 9Use of the intestinal and hepatic bile acid transporters for drug deliveryAdvanced Drug Delivery Reviews, Vol. 20, No. 1Intestinal Transport of Bile Acids1 January 2011Active absorption of conjugated bile acids in vivoGastroenterology, Vol. 100, No. 1Effect of chronic administration of ursodeoxycholic acid on the ileal absorption of endogenous bile acids in manHepatology, Vol. 12, No. 5Serum Bile AcidsUtilizing Bile Acid Carrier Mechanisms to Enhance Liver and Small Intestine AbsorptionAnnals of the New York Academy of Sciences, Vol. 507, No. 1 Biological ApIleal absorption of tyrosine-conjugated bile acids in Wistar ratsBiochimica et Biophysica Acta (BBA) - General Subjects, Vol. 926, No. 2Simulation of the metabolism and enterohepatic circulation of endogenous deoxycholic acid in humans using a physiologic pharmacokinetic model for bile acid metabolismGastroenterology, Vol. 93, No. 4Simulation of the metabolism and enterohepatic circulation of endogenous chenodeoxycholic acid in man using a physiological pharmacokinetic modelEuropean Journal of Clinical Investigation, Vol. 16, No. 5Kinetics of Taurocholate Uptake by Isolated Ileal Cells of Guinea PigEuropean Journal of Biochemistry, Vol. 131, No. 2Resorption von GallensäurenBile acid uptake by isolated intestinal mucosa cells of guinea pigBiochimica et Biophysica Acta (BBA) - Molecular Cell Research, Vol. 721, No. 3Properties and biological significance of the ileal bile salt transport system.Environmental Health Perspectives, Vol. 33Pathophysiology of the enterohepatic circulation of bile acids21 June 2005Bile Salt Metabolism:I. The Physiology of Bile Salts25 March 2008 | Australian and New Zealand Journal of Medicine, Vol. 7, No. 6Interaction of uncharged bile salt derivatives with the ileal bile salt transport systemJournal of Lipid Research, Vol. 18, No. 3Dynamics of the Enterohepatic Circulation of the Glycine Conjugates of Cholic, Chenodeoxycholic, Deoxycholic, and Sulfolithocholic Acid in ManGastroenterology, Vol. 72, No. 3Ionic requirements for the active ileal bile salt transport systemJournal of Lipid Research, Vol. 17, No. 6Regional Ileitis (Crohn’s Disease)16 October 2020 | Scandinavian Journal of Gastroenterology, Vol. 11, No. 5Characterization of the passive and active transport mechanisms for bile acid uptake into rat isolated intestinal epithelial cellsBiochimica et Biophysica Acta (BBA) - Biomembranes, Vol. 406, No. 2Interactions of cationic bile salt derivatives with the ileal bile salt transport system.Journal of Lipid Research, Vol. 16, No. 5Effects of meals and interruption of enterohepatic circulation on flow, lipid composition, and cholesterol saturation of bile in man after cholecystectomyThe American Journal of Digestive Diseases, Vol. 20, No. 2Effect of Phenobarbital on Intestinal Cholic Acid Absorption in the RatGastroenterology, Vol. 67, No. 6Bile Salt Transport SystemsIleal transport of bile acids conjugated with norleucine and lysineBiochimica et Biophysica Acta (BBA) - Biomembranes, Vol. 266, No. 1Transport of DrugsThe Enterohepatic CirculationGastroenterology, Vol. 62, No. 1Metabolism and transport of bile salts in the intestineThe American Journal of Medicine, Vol. 51, No. 5Changes in Fat Absorption following small Bowel Resection in the Dog27 September 2008 | Archives Internationales de Physiologie et de Biochimie, Vol. 79, No. 5Morphological changes of the small-intestinal mucosa of guinea pig and hamster following incubation in vitro and perfusion in vivo with unconjugated bile saltsGut, Vol. 11, No. 6Effects of Sulfation of Taurolithocholic and Glycolithocholic Acids on their Intestinal TransportGastroenterology, Vol. 56, No. 4 More from this issue > Volume 214Issue 3March 1968Pages 585-590 Copyright & PermissionsCopyright © 1968 by American Physiological Societyhttps://doi.org/10.1152/ajplegacy.1968.214.3.585PubMed5644097History Published online 1 March 1968 Published in print 1 March 1968 Metrics