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Metabolic Profile of Obeticholic Acid and Endogenous Bile Acids in Rats with Decompensated Liver Cirrhosis.

ABSTRACT: Obeticholic acid (OCA) is a semisynthetic bile acid (BA) analog and potent farnesoid X receptor agonist approved to treat cholestasis. We evaluated the biodistribution and metabolism of OCA administered to carbon tetrachloride-induced cirrhotic rats. This was to ascertain if plasma and hepatic concentrations of OCA are potentially more harmful than those of endogenous BAs. After administration of OCA (30 mg/kg), we used liquid chromatography-mass spectrometry to measure OCA, its metabolites, and BAs at different timepoints in various organs and fluids. Plasma and hepatic concentrations of OCA and BAs were higher in cirrhotic rats than in controls. OCA and endogenous BAs had similar metabolic pathways in cirrhotic rats, although OCA hepatic and intestinal clearance were lower than in controls. BAs' qualitative and quantitative compositions were not modified by a single administration of OCA. In all the matrices studied, OCA concentrations were significantly lower than those of endogenous BAs, potentially much more cytotoxic.

SUBMITTER: Roda A

PROVIDER: S-EPMC5504479 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Metabolic Profile of Obeticholic Acid and Endogenous Bile Acids in Rats with Decompensated Liver Cirrhosis.

Roda A A Aldini R R Camborata C C Spinozzi S S Franco P P Cont M M D'Errico A A Vasuri F F Degiovanni A A Maroni L L Adorini L L

Clinical and translational science 20170523 4

Obeticholic acid (OCA) is a semisynthetic bile acid (BA) analog and potent farnesoid X receptor agonist approved to treat cholestasis. We evaluated the biodistribution and metabolism of OCA administered to carbon tetrachloride-induced cirrhotic rats. This was to ascertain if plasma and hepatic concentrations of OCA are potentially more harmful than those of endogenous BAs. After administration of OCA (30 mg/kg), we used liquid chromatography-mass spectrometry to measure OCA, its metabolites, and ...[more]

PMID: 28411380

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Project description:The accumulation of toxic bile acids (BAs) is closely related to liver injury, inflammation and tumorigenesis. The aim of the present study was to determine the role of the serum BA spectrum in the diagnosis and progression of liver cirrhosis. This was a prospective observational study involving patients with chronic hepatitis (n=23), liver cirrhosis (n=101), and cirrhosis complicated with hepatocellular carcinoma (CC-HCC; n=56). The 6-month survival of cirrhotic patients was recorded after blood collection. Comparisons of serum total BAs and individual BAs between different groups were performed using the Mann-Whitney U or Kruskal-Wallis tests. Correlation analysis was conducted by Spearman's correlation. Diagnosis and prediction analyses were performed using receiver operating characteristic curves. Survival was analyzed using the Kaplan-Meier method and multivariable Cox regression analysis. The concentrations of total BAs, glycocholic acid (GCA), glycochenodeoxycholic acid (GCDCA), taurocholic acid (TCA), taurochenoxycholic acid and tauroursodeoxycholic acid (TUDCA) were increased significantly in patients with early cirrhosis compared to patients with chronic hepatitis (P<0.05) and were associated with the diagnosis of cirrhosis (P=0.049, 0.004, 0.002, 0.003, 0.010 and 0.009, respectively). The levels of total BAs, primary conjugated BAs, and TUDCA increased as liver cirrhosis progressed (P<0.05). Serum total BAs, GCA, GCDCA, and TCA predicted the 6-month survival of patients with liver cirrhosis (P=0.0003, 0.005, 0.002, and 0.010 respectively). Based on multivariate Cox regression analysis, the level of total BAs was an independent predictor of mortality in cirrhotic patients (hazard ratios, 4.046; 95% CI, 1.620-10.108; P=0.003). In the early-stage cirrhosis group, the concentrations of total BAs and primary conjugated BAs were significantly elevated in patients with CC-HCC compared with patients with cirrhosis alone. In conclusion, total and individual BAs, especially primary conjugated BAs, are effective non-invasive markers in the diagnosis and prognosis of liver cirrhosis, and may be potential indicators in the occurrence of hepatocellular carcinoma in patients with early cirrhosis.

Project description:Intrahepatic cholestasis of pregnancy (ICP) is characterized by elevated maternal circulating bile acid levels and associated dyslipidemia. ICP leads to accumulation of bile acids in the fetal compartment, and the elevated bile acid concentrations are associated with an increased risk of adverse fetal outcomes. The farnesoid X receptor agonist obeticholic acid (OCA) is efficient in the treatment of cholestatic conditions such as primary biliary cholangitis. We hypothesized that OCA administration during hypercholanemic pregnancy will improve maternal and fetal bile acid and lipid profiles. Female C57BL/6J mice were fed either a normal chow diet, a 0.5% cholic acid (CA)-supplemented diet, a 0.03% OCA-supplemented diet, or a 0.5% CA + 0.03% OCA-supplemented diet for 1 wk before mating and throughout pregnancy until euthanization on day 18. The effects of CA and OCA feeding on maternal and fetal morphometry, bile acid and lipid levels, and cecal microbiota were investigated. OCA administration during gestation did not alter the maternal or fetal body weight or organ morphometry. OCA treatment during hypercholanemic pregnancy reduced bile acid levels in the fetal compartment. However, fetal dyslipidemia was not reversed, and OCA did not impact maternal bile acid levels or dyslipidemia. In conclusion, OCA administration during gestation had no apparent detrimental impact on maternal or fetal morphometry and improved fetal hypercholanemia. Because high serum bile acid concentrations in ICP are associated with increased rates of adverse fetal outcomes, further investigations into the potential use of OCA during cholestatic gestation are warranted.NEW & NOTEWORTHY We used a mouse model of gestational hypercholanemia to investigate the use of obeticholic acid (OCA), a potent FXR agonist, as a treatment for the hypercholanemia of intrahepatic cholestasis of pregnancy (ICP). The results demonstrate that OCA can improve the fetal bile acid profile. This is relevant not only to women with ICP but also for women who become pregnant while receiving OCA treatment for other conditions such as primary biliary cholangitis and nonalcoholic steatohepatitis.

Dataset Information

Metabolic Profile of Obeticholic Acid and Endogenous Bile Acids in Rats with Decompensated Liver Cirrhosis.

Publications

Metabolic Profile of Obeticholic Acid and Endogenous Bile Acids in Rats with Decompensated Liver Cirrhosis.

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