Effect of ursodeoxycholic acid on bile acid profiles and intestinal detoxification machinery in primary biliary cirrhosis and health

• Published in: Journal of hepatology Vol. 57; no. 1; pp. 133 - 140
• Main Authors: Dilger, Karin, Hohenester, Simon, Winkler-Budenhofer, Ursula, Bastiaansen, Barbara A.J., Schaap, Frank G., Rust, Christian, Beuers, Ulrich
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier B.V 01.07.2012; Elsevier
• Subjects: Adult; Bile; Bile Acids and Salts - blood; Biliary Tract - drug effects; Biliary Tract - metabolism; Biological and medical sciences; Biotransformation; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cholagogues and Choleretics - administration & dosage; Cholagogues and Choleretics - blood; Cholagogues and Choleretics - pharmacokinetics; Cholestasis; Cholestasis - drug therapy; Cholestasis - metabolism; Clinical trial; Cytochrome P-450 CYP3A - genetics; Cytochrome P-450 CYP3A - metabolism; Drug transport; Duodenum - drug effects; Duodenum - metabolism; Female; Gastroenterology and Hepatology; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression Profiling; Glycine - blood; Humans; Inactivation, Metabolic - physiology; Intestinal Mucosa - metabolism; Liver Cirrhosis, Biliary - drug therapy; Liver Cirrhosis, Biliary - metabolism; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Medical sciences; Middle Aged; Other diseases. Semiology; Taurine - blood; Ursodeoxycholic Acid - administration & dosage; Ursodeoxycholic Acid - blood; Ursodeoxycholic Acid - pharmacokinetics; FXR; PTF; RXRα; TUDCA; UDCA; MRP; PXR; GCDCA; AE2; PBC; SLCA; MDR1; Biotransformation; AUC0–24h; Clinical trial; ASBT; GDCA; CYP; CA; UGT1A7; SULT2A1; CDCA; BCRP; Cmax; Drug transport; GLCA; DCA; GUDCA; GCA; ABCC7; VDR; TDCA; OATP; OSTα/OSTβ; LCA; TCDCA; PPARα; GlnUDCA; TLCA; TCA; CAR; SUDCA; Cholestasis; Bile; cholic acid; taurocholic acid; anion exchanger 2; retinoid X receptor alpha; pregnane X receptor; deoxycholic acid; AUC 0–24 h; multidrug resistance 1; peak-trough-fluctuation; tauroursodeoxycholic acid; lithocholic acid-3-sulfate; primary biliary cirrhosis; glycochenodeoxycholic acid; vitamin D receptor; apical sodium-dependent bile acid transporter; area under the plasma concentration-time curve during 24 h; breast cancer resistance protein; organic solute transporter α/β; glycocholic acid; lithocholic acid; taurolithocholic acid; taurochenodeoxycholic acid; glycodeoxycholic acid; glycolithocholic acid; taurodeoxycholic acid; organic anion transporting polypeptide; C max; cystic fibrosis transmembrane conductance regulator (ATP-binding cassette sub-family C member 7); multidrug resistance associated protein; ursodeoxycholic acid; peroxisome proliferator-activated receptor alpha; glycoursodeoxycholic acid; ursodeoxycholic acid-3-beta-glucuronide; peak plasma concentration; farnesoid X receptor; bile-salt sulfotransferase 2A1; ursodeoxycholic acid-3-sulfate; cytochrome P450; constitutive androstane receptor; chenodeoxycholic acid; UDP-glucuronosyltransferase 1 family polypeptide A7; Primary biliary cirrhosis; Detoxification; Gut; Hepatic disease; Biliary tract disease; Ursodeoxycholic acid; Bile acid; Cholostasis; Gastroenterology; Digestive diseases
• ISSN: 0168-8278; 1600-0641; 1600-0641
• DOI: 10.1016/j.jhep.2012.02.014

Ursodeoxycholic acid (UDCA) exerts anticholestatic, antifibrotic and antiproliferative effects in primary biliary cirrhosis (PBC) via mechanisms not yet fully understood. Its adequate biliary enrichment is considered mandatory for therapeutic efficacy. However, precise determination of biliary enrichment of UDCA is not possible in clinical practice. Therefore, we investigated (i) the relationship between biliary enrichment and plasma pharmacokinetics of UDCA, (ii) the effect of UDCA on plasma and biliary bile acid composition and conjugation patterns, and (iii) on the intestinal detoxification machinery in patients with PBC and healthy controls. In 11 PBC patients and 11 matched healthy subjects, cystic bile and duodenal tissue were collected before and after 3weeks of administration of UDCA (15mg/kg/day). Extensive pharmacokinetic profiling of bile acids was performed. The effect of UDCA on the intestinal detoxification machinery was studied by quantitative PCR and Western blotting. The relative fraction of UDCA and its conjugates in plasma at trough level[x] correlated with their biliary enrichment[y] (r=0.73, p=0.0001, y=3.65+0.49x). Taurine conjugates of the major hydrophobic bile acid, chenodeoxycholic acid, were more prominent in bile of PBC patients than in that of healthy controls. Biliary bile acid conjugation patterns normalized after treatment with UDCA. UDCA induced duodenal expression of key export pumps, BCRP and P-glycoprotein. Biliary and trough plasma enrichment of UDCA are closely correlated in PBC and health. Taurine conjugation may represent an adaptive mechanism in PBC against chenodeoxycholic acid-mediated bile duct damage. UDCA may stabilize small intestinal detoxification by upregulation of efflux pumps.