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Latest development in the synthesis of ursodeoxycholic acid (UDCA): a critical review.

ABSTRACT: Ursodeoxycholic acid (UDCA) is a pharmaceutical ingredient widely used in clinics. As bile acid it solubilizes cholesterol gallstones and improves the liver function in case of cholestatic diseases. UDCA can be obtained from cholic acid (CA), which is the most abundant and least expensive bile acid available. The now available chemical routes for the obtainment of UDCA yield about 30% of final product. For these syntheses several protection and deprotection steps requiring toxic and dangerous reagents have to be performed, leading to the production of a series of waste products. In many cases the cholic acid itself first needs to be prepared from its taurinated and glycilated derivatives in the bile, thus adding to the complexity and multitude of steps involved of the synthetic process. For these reasons, several studies have been performed towards the development of microbial transformations or chemoenzymatic procedures for the synthesis of UDCA starting from CA or chenodeoxycholic acid (CDCA). This promising approach led several research groups to focus their attention on the development of biotransformations with non-pathogenic, easy-to-manage microorganisms, and their enzymes. In particular, the enzymatic reactions involved are selective hydrolysis, epimerization of the hydroxy functions (by oxidation and subsequent reduction) and the specific hydroxylation and dehydroxylation of suitable positions in the steroid rings. In this minireview, we critically analyze the state of the art of the production of UDCA by several chemical, chemoenzymatic and enzymatic routes reported, highlighting the bottlenecks of each production step. Particular attention is placed on the precursors availability as well as the substrate loading in the process. Potential new routes and recent developments are discussed, in particular on the employment of flow-reactors. The latter technology allows to develop processes with shorter reaction times and lower costs for the chemical and enzymatic reactions involved.

SUBMITTER: Tonin F

PROVIDER: S-EPMC5827811 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Latest development in the synthesis of ursodeoxycholic acid (UDCA): a critical review.

Tonin Fabio F Arends Isabel W C E IWCE

Beilstein journal of organic chemistry 20180220

Ursodeoxycholic acid (UDCA) is a pharmaceutical ingredient widely used in clinics. As bile acid it solubilizes cholesterol gallstones and improves the liver function in case of cholestatic diseases. UDCA can be obtained from cholic acid (CA), which is the most abundant and least expensive bile acid available. The now available chemical routes for the obtainment of UDCA yield about 30% of final product. For these syntheses several protection and deprotection steps requiring toxic and dangerous re ...[more]

PMID: 29520309

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Project description:BackgroundTreatment guidelines recommend a stepwise approach to primary biliary cholangitis: all patients begin treatment with ursodeoxycholic acid (UDCA) monotherapy and those with an inadequate biochemical response after 12 months are subsequently considered for second-line therapies. However, as a result, patients at the highest risk can wait the longest for effective treatment. We determined whether UDCA response can be accurately predicted using pretreatment clinical parameters.MethodsWe did logistic regression analysis of pretreatment variables in a discovery cohort of patients in the UK with primary biliary cholangitis to derive the best-fitting model of UDCA response, defined as alkaline phosphatase less than 1·67 times the upper limit of normal (ULN), measured after 12 months of treatment with UDCA. We validated the model in an external cohort of patients with primary biliary cholangitis and treated with UDCA in Italy. Additionally, we assessed correlations between model predictions and key histological features, such as biliary injury and fibrosis, on liver biopsy samples.Findings2703 participants diagnosed with primary biliary cholangitis between Jan 1, 1998, and May 31, 2015, were included in the UK-PBC cohort for derivation of the model. The following pretreatment parameters were associated with lower probability of UDCA response: higher alkaline phosphatase concentration (p<0·0001), higher total bilirubin concentration (p=0·0003), lower aminotransferase concentration (p=0·0012), younger age (p<0·0001), longer interval from diagnosis to the start of UDCA treatment (treatment time lag, p<0·0001), and worsening of alkaline phosphatase concentration from diagnosis (p<0·0001). Based on these variables, we derived a predictive score of UDCA response. In the external validation cohort, 460 patients diagnosed with primary biliary cholangitis were treated with UDCA, with follow-up data until May 31, 2016. In this validation cohort, the area under the receiver operating characteristic curve for the score was 0·83 (95% CI 0·79-0·87). In 20 liver biopsy samples from patients with primary biliary cholangitis, the UDCA response score was associated with ductular reaction (r=-0·556, p=0·0130) and intermediate hepatocytes (probability of response was 0·90 if intermediate hepatocytes were absent vs 0·51 if present).InterpretationWe have derived and externally validated a model based on pretreatment variables that accurately predicts UDCA response. Association with histological features provides face validity. This model provides a basis to explore alternative approaches to treatment stratification in patients with primary biliary cholangitis.FundingUK Medical Research Council and University of Milan-Bicocca.

Project description:It has been previously reported that ursodeoxycholic acid (UDCA), a therapeutic bile acid, reduced risk for advanced colorectal adenoma in men but not women. Interactions between the gut microbiome and fecal bile acid composition as a factor in colorectal cancer neoplasia have been postulated but evidence is limited to small cohorts and animal studies. Using banked stool samples collected as part of a phase III randomized clinical trial of UDCA for the prevention of colorectal adenomatous polyps, we compared change in the microbiome composition after a 3-year intervention in a subset of participants randomized to oral UDCA at 8-10 mg/kg of body weight per day (n = 198) or placebo (n = 203). Study participants randomized to UDCA experienced compositional changes in their microbiome that were statistically more similar to other individuals in the UDCA arm than to those in the placebo arm. This reflected a UDCA-associated shift in microbial community composition (P < 0.001), independent of sex, with no evidence of a UDCA effect on microbial richness (P > 0.05). These UDCA-associated shifts in microbial community distance metrics from baseline to end-of-study were not associated with risk of any or advanced adenoma (all P > 0.05) in men or women. Separate analyses of microbial networks revealed an overrepresentation of Faecalibacterium prausnitzii in the post-UDCA arm and an inverse relationship between F prausnitzii and Ruminococcus gnavus. In men who received UDCA, the overrepresentation of F prausnitzii and underrepresentation of R gnavus were more prominent in those with no adenoma recurrence at follow-up compared to men with recurrence. This relationship was not observed in women. Daily UDCA use modestly influences the relative abundance of microbial species in stool and affects the microbial network composition with suggestive evidence for sex-specific effects of UDCA on stool microbial community composition as a modifier of colorectal adenoma risk.

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Latest development in the synthesis of ursodeoxycholic acid (UDCA): a critical review.

Publications

Latest development in the synthesis of ursodeoxycholic acid (UDCA): a critical review.

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