Obeticholic acid
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Identification
- Summary
Obeticholic acid is a bile acid analog and farnesoid X receptor agonist used to treat primary biliary cholangitis in adult patients with inadequate clinical response or intolerance to UDCA.
- Brand Names
- Ocaliva
- Generic Name
- Obeticholic acid
- DrugBank Accession Number
- DB05990
- Background
Primary biliary cirrhosis, or PBC, is a progressive and chronic condition that leads to hepatic injury often resulting in end-stage liver failure that requires liver transplantation.3
Obeticholic acid is a farnesoid-X receptor (FXR) agonist used to treat this condition, possibly allowing for increased survival.1 In 2016, it was granted approval to treat primary biliary cholangitis in combination with ursodeoxycholic acid, which was previously the mainstay treatment for this condition.1,9 In May 2021, the FDA updated its prescribing information to contraindicate the use of obeticholic acid in patients with PBC and advanced cirrhosis (e.g. those with portal hypertension or hepatic decompensation) due to a risk of liver failure, in some cases requiring liver transplantation.14
Obeticholic acid is currently being considered for FDA approval to treat fibrosis caused by non-alcoholic liver steatohepatitis (NASH). The NDA from Intercept Pharmaceuticals was approved in November 2019 and obeticholic acid is expected to be granted full approval for this indication in 2020.10
- Type
- Small Molecule
- Groups
- Approved
- Structure
- Weight
- Average: 420.6252
Monoisotopic: 420.323959896 - Chemical Formula
- C26H44O4
- Synonyms
- (3α,5β,6α,7α)-6-ethyl-3,7-dihydroxycholan-24-oic acid
- 6-alpha-ethylchenodeoxycholic acid
- 6-ECDCA
- 6-Ethyl-CDCA
- 6-ethylchenodeoxycholic acid
- 6alpha-Ethyl-chenodeoxycholic acid
- 6α-ethylchenodeoxycholic acid
- Obeticholic acid
- External IDs
- DSP-1747
- INT 747
- INT-747
- INT747
Pharmacology
- Indication
Obeticholic acid is indicated for the treatment of primary biliary cholangitis in combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA. It is also used as a monotherapy in adults with PBC that are unable to tolerate UDCA.9
Obeticholic acid is currently being considered for FDA approval to treat fibrosis caused by non-alcoholic liver steatohepatitis (NASH), and is likely to be approved for this indication in 2020.10
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Used in combination to treat Primary biliary cholangitis Regimen in combination with: Ursodeoxycholic acid (DB01586) •••••••••••• •••••••••• •••••••• •• •••• •••••••••••••••• ••••• •••••• Treatment of Primary biliary cholangitis •••••••••••• •••••• •• •••••••• ••••••••••••••• •••• •••••• •••••• - Contraindications & Blackbox Warnings
- Prevent Adverse Drug Events TodayTap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events with our Clinical API
- Pharmacodynamics
The activation of the FXR by obeticholic acid acts to reduce the synthesis of bile acids, inflammation, and the resulting hepatic fibrosis. This may increase the survival of patients with PBC, but to date, an association between obeticholic acid and survival in PBC has not been established.3,9
- Mechanism of action
Primary biliary cirrhosis is an autoimmune process by which the bile ducts and liver are damaged progressively, leading to fibrosis and cirrhosis. Bile acids increase the risk of damage and fibrosis to the damaged bile ducts.3,5
Obeticholic acid is a potent agonist of the farnesoid X receptor, which serves to regulate the hepatic metabolism of bile and cholesterol. This drug acts by binding to the farnesoid X receptor (FXR), found in the nucleus of liver and intestinal cells, which in turn increases liver bile flow, suppressing its production and decreasing hepatocyte exposure to excess levels of bile with cholestasis. Cholestasis is a process that normally causes inflammation and cirrhosis of the liver.4,9
Target Actions Organism ABile acid receptor agonistHumans - Absorption
Obeticholic acid is absorbed in the gastrointestinal tract. The Cmax of obeticholic acid occurs at approximately 1.5 hours after an oral dose and ranges from 28.8-53.7 ng/mL at doses of 5-10mg.12 The median Tmax for both the conjugates of obeticholic acid is about 10 hours.9 One product monograph reports a Tmax of 4.5h for both 5 and 10mg doses. The AUC ranged from 236.6-568.1 ng/h/mL with 5mg to 10 mg doses.12
- Volume of distribution
The volume of distribution of obeticholic acid is 618 L.9,11
- Protein binding
Obeticholic acid and its metabolic conjugates are >99% plasma protein-bound.9,11
- Metabolism
The metabolism of obeticholic acid occurs in the liver. Obeticholic acid is conjugated with glycine or taurine, followed by secretion into bile. The conjugates are then absorbed in the small intestine and then re-enter the liver via enterohepatic circulation. The intestinal microbiota in the ileum converts conjugated obeticholic acid in a deconjugated form that may be either reabsorbed or eliminated. Glycine conjugates account for 13.8% of the metabolites and taurine conjugates account for 12.3%. Another metabolite, 3-glucuronide, may also be formed, but displays little pharmacological activity.9
- Route of elimination
About 87% of an orally administered dose is accounted for in the feces. Less than 3% of the dose can be recovered in the urine.9,11
- Half-life
The biological half-life of obeticholic acid is reported to be 24 hours.13
- Clearance
Clearance information for obeticholic acid is not readily available in the literature.9,11
- Adverse Effects
- Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!Improve decision support & research outcomes with our structured adverse effects data.
- Toxicity
LD50 information for obeticholic acid is not readily available in the literature.9
The maximum documented exposure to obeticholic acid was 500 mg in healthy research volunteers. Doses of 250 mg have been administered to healthy volunteers for 12 consecutive days. Pruritus and reversible transaminase liver elevations were observed. In PBC patients who received 25mg daily to 50mg daily (2.5 to 5 times the maximum recommended dose), dose-dependent transaminase and bilirubin elevations, ascites, primary biliary cholangitis aggravation, and new-onset jaundice were reported.11
In the case of an overdose with obeticholic acid, clinical monitoring and supportive care should be offered as they are required.11
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwareAbciximab The risk or severity of adverse effects can be increased when Abciximab is combined with Obeticholic acid. Acenocoumarol The therapeutic efficacy of Acenocoumarol can be decreased when used in combination with Obeticholic acid. Acetaminophen The metabolism of Acetaminophen can be decreased when combined with Obeticholic acid. Acetylsalicylic acid The risk or severity of adverse effects can be increased when Acetylsalicylic acid is combined with Obeticholic acid. Acyclovir The metabolism of Acyclovir can be decreased when combined with Obeticholic acid. - Food Interactions
- Take with or without food.
Products
- Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.
- International/Other Brands
- Ocaliva
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Ocaliva Tablet, film coated 10 mg Oral Advanz Pharma Limited 2020-12-16 Not applicable EU Ocaliva Tablet, film coated 5 mg Oral Advanz Pharma Limited 2020-12-16 Not applicable EU Ocaliva Tablet, film coated 10 mg/1 Oral Intercept Pharmaceuticals Inc 2016-05-27 Not applicable US Ocaliva Tablet, film coated 5 mg Oral Advanz Pharma Limited 2020-12-16 Not applicable EU Ocaliva Tablet 10 mg Oral Advanz Pharma Limited 2017-05-26 Not applicable Canada
Categories
- ATC Codes
- A05AA04 — Obeticholic acid
- Drug Categories
- Alimentary Tract and Metabolism
- Bile Acid Preparations
- Bile acids and derivatives
- Bile Acids and Salts
- Bile and Liver Therapy
- Bile Therapy
- BSEP/ABCB11 inducers
- BSEP/ABCB11 Inhibitors
- Cholanes
- Cholic Acids
- Cytochrome P-450 CYP1A2 Inhibitors
- Cytochrome P-450 CYP1A2 Inhibitors (strength unknown)
- Cytochrome P-450 Enzyme Inhibitors
- Farnesoid X Receptor Agonist
- Farnesoid X Receptor Agonists
- Fused-Ring Compounds
- Miscellaneous GI Drugs
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as dihydroxy bile acids, alcohols and derivatives. These are compounds containing or derived from a bile acid or alcohol, and which bears exactly two carboxylic acid groups.
- Kingdom
- Organic compounds
- Super Class
- Lipids and lipid-like molecules
- Class
- Steroids and steroid derivatives
- Sub Class
- Bile acids, alcohols and derivatives
- Direct Parent
- Dihydroxy bile acids, alcohols and derivatives
- Alternative Parents
- 7-hydroxysteroids / 3-alpha-hydroxysteroids / Secondary alcohols / Cyclic alcohols and derivatives / Monocarboxylic acids and derivatives / Carboxylic acids / Organic oxides / Hydrocarbon derivatives / Carbonyl compounds
- Substituents
- 3-alpha-hydroxysteroid / 3-hydroxysteroid / 7-hydroxysteroid / Alcohol / Aliphatic homopolycyclic compound / Carbonyl group / Carboxylic acid / Carboxylic acid derivative / Cyclic alcohol / Dihydroxy bile acid, alcohol, or derivatives
- Molecular Framework
- Aliphatic homopolycyclic compounds
- External Descriptors
- cholanoid (CHEBI:43602)
- Affected organisms
- Not Available
Chemical Identifiers
- UNII
- 0462Z4S4OZ
- CAS number
- 459789-99-2
- InChI Key
- ZXERDUOLZKYMJM-ZWECCWDJSA-N
- InChI
- InChI=1S/C26H44O4/c1-5-17-21-14-16(27)10-12-26(21,4)20-11-13-25(3)18(15(2)6-9-22(28)29)7-8-19(25)23(20)24(17)30/h15-21,23-24,27,30H,5-14H2,1-4H3,(H,28,29)/t15-,16-,17-,18-,19+,20+,21+,23+,24-,25-,26-/m1/s1
- IUPAC Name
- (4R)-4-[(1R,3aS,3bS,4R,5R,5aS,7R,9aS,9bS,11aR)-5-ethyl-4,7-dihydroxy-9a,11a-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-1-yl]pentanoic acid
- SMILES
- [H][C@@]1(CC[C@@]2([H])[C@]3([H])[C@H](O)[C@H](CC)[C@]4([H])C[C@H](O)CC[C@]4(C)[C@@]3([H])CC[C@]12C)[C@H](C)CCC(O)=O
References
- Synthesis Reference
He XL, Wang LT, Gu XZ, Xiao JX, Qiu WW. A facile synthesis of ursodeoxycholic acid and obeticholic acid from cholic acid.J.steroids.2018.10.009. Epub 2018 Oct 31.
- General References
- Markham A, Keam SJ: Obeticholic Acid: First Global Approval. Drugs. 2016 Aug;76(12):1221-6. doi: 10.1007/s40265-016-0616-x. [Article]
- Eslam M, Alvani R, Shiha G: Obeticholic acid: towards first approval for NASH. Lancet. 2019 Dec 14;394(10215):2131-2133. doi: 10.1016/S0140-6736(19)32963-0. Epub 2019 Dec 5. [Article]
- Manne V, Kowdley KV: Obeticholic acid in primary biliary cholangitis: where we stand. Curr Opin Gastroenterol. 2019 May;35(3):191-196. doi: 10.1097/MOG.0000000000000525. [Article]
- Jones DE: Pathogenesis of primary biliary cirrhosis. Gut. 2007 Nov;56(11):1615-24. doi: 10.1136/gut.2007.122150. Epub 2007 Jul 19. [Article]
- Onofrio FQ, Hirschfield GM, Gulamhusein AF: A Practical Review of Primary Biliary Cholangitis for the Gastroenterologist. Gastroenterol Hepatol (N Y). 2019 Mar;15(3):145-154. [Article]
- Bowlus CL: Obeticholic acid for the treatment of primary biliary cholangitis in adult patients: clinical utility and patient selection. Hepat Med. 2016 Sep 1;8:89-95. doi: 10.2147/HMER.S91709. eCollection 2016. [Article]
- Edwards JE, LaCerte C, Peyret T, Gosselin NH, Marier JF, Hofmann AF, Shapiro D: Modeling and Experimental Studies of Obeticholic Acid Exposure and the Impact of Cirrhosis Stage. Clin Transl Sci. 2016 Dec;9(6):328-336. doi: 10.1111/cts.12421. Epub 2016 Oct 15. [Article]
- MSDS [Link]
- FDA Approved Products: Ocaliva (obeticholic acid) oral tablets [Link]
- FDA Accepts Intercept’s NDA for OCA for the Treatment of Liver Fibrosis Due to NASH and Grants Priority Review [Link]
- EMA Summary of product characteristics, Ocaliva (obeticholic acid) 5 and 10 mg oral tablets [Link]
- Product Monograph: Ocaliva (obeticholic acid) oral tablets [Link]
- NIH InXight Drugs: Obeticholic acid [Link]
- FDA Drug Safety Communication: Due to risk of serious liver injury, FDA restricts use of Ocaliva (obeticholic acid) in primary biliary cholangitis (PBC) patients with advanced cirrhosis [Link]
- External Links
- KEGG Drug
- D09360
- KEGG Compound
- C15636
- PubChem Compound
- 447715
- PubChem Substance
- 347827752
- ChemSpider
- 394730
- BindingDB
- 21675
- 1798288
- ChEBI
- 43602
- ChEMBL
- CHEMBL566315
- ZINC
- ZINC000014164617
- PDBe Ligand
- CHC
- Wikipedia
- Obeticholic_acid
- PDB Entries
- 1osv / 1ot7
- FDA label
- Download (5.07 MB)
Clinical Trials
- Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample dataNot Available Completed Not Available Primary Biliary Cholangitis 1 somestatus stop reason just information to hide Not Available Completed Other Consumption, Alcohol 1 somestatus stop reason just information to hide Not Available Completed Treatment Fatty Liver, Non-alcoholic Fatty Liver Disease, NAFLD 1 somestatus stop reason just information to hide Not Available Recruiting Not Available Primary Bilary Cirrhosis (PBC) / Primary Biliary Cholangitis 1 somestatus stop reason just information to hide Not Available Recruiting Other Healthy Volunteers (HV) 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet Oral 10 mg Tablet Oral 5 mg Tablet, film coated Oral 10 mg/1 Tablet, film coated Oral 10 MG Tablet, film coated Oral 5 MG Tablet, film coated Oral 5 mg/1 - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US7138390 No 2006-11-21 2022-11-16 US US9238673 No 2016-01-19 2033-06-17 US US8058267 No 2011-11-15 2022-02-21 US US8377916 No 2013-02-19 2022-02-21 US US10052337 No 2018-08-21 2036-04-26 US US10047117 No 2018-08-14 2033-09-06 US US10174073 No 2019-01-08 2033-06-17 US US10751349 No 2020-08-25 2036-04-26 US US10758549 No 2020-09-01 2036-04-26 US USRE48286 No 2020-10-27 2027-11-16 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source melting point (°C) 108-110 https://www.chemicalbook.com/ChemicalProductProperty_EN_CB92484652.htm boiling point (°C) 562.9±25 https://www.chemicalbook.com/ChemicalProductProperty_EN_CB92484652.htm logP 5.11 https://www.ebi.ac.uk/chembl/compound_report_card/CHEMBL566315/ pKa 4.76±0.10 https://www.chemicalbook.com/ChemicalProductProperty_EN_CB92484652.htm - Predicted Properties
Property Value Source Water Solubility 0.011 mg/mL ALOGPS logP 3.5 ALOGPS logP 4.52 Chemaxon logS -4.6 ALOGPS pKa (Strongest Acidic) 4.6 Chemaxon pKa (Strongest Basic) -0.16 Chemaxon Physiological Charge -1 Chemaxon Hydrogen Acceptor Count 4 Chemaxon Hydrogen Donor Count 3 Chemaxon Polar Surface Area 77.76 Å2 Chemaxon Rotatable Bond Count 5 Chemaxon Refractivity 118.35 m3·mol-1 Chemaxon Polarizability 49.74 Å3 Chemaxon Number of Rings 4 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-0uk9-0008900000-c33af5291860a90600ad Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-014i-0000900000-079fa53b8b7590d7c953 Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-0kmj-7809500000-34757919f4f805c78ffc Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-014i-0001900000-69eba84235e21d830b4b Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-0q2a-2009300000-5b035fe6b704112a5010 Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-0ab9-3940100000-8d1aea3963492d9954f8 Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 211.4223965 predictedDarkChem Lite v0.1.0 [M-H]- 182.05605 predictedDeepCCS 1.0 (2019) [M+H]+ 210.1519965 predictedDarkChem Lite v0.1.0 [M+H]+ 183.77975 predictedDeepCCS 1.0 (2019) [M+Na]+ 208.3682965 predictedDarkChem Lite v0.1.0 [M+Na]+ 190.06117 predictedDeepCCS 1.0 (2019)
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Agonist
- Curator comments
- Also known as FXR receptor.
- General Function
- Ligand-activated transcription factor. Receptor for bile acids (BAs) such as chenodeoxycholic acid (CDCA), lithocholic acid, deoxycholic acid (DCA) and allocholic acid (ACA). Plays a essential role in BA homeostasis through the regulation of genes involved in BA synthesis, conjugation and enterohepatic circulation. Also regulates lipid and glucose homeostasis and is involved innate immune response (PubMed:10334992, PubMed:10334993, PubMed:21383957, PubMed:22820415). The FXR-RXR heterodimer binds predominantly to farnesoid X receptor response elements (FXREs) containing two inverted repeats of the consensus sequence 5'-AGGTCA-3' in which the monomers are spaced by 1 nucleotide (IR-1) but also to tandem repeat DR1 sites with lower affinity, and can be activated by either FXR or RXR-specific ligands. It is proposed that monomeric nuclear receptors such as NR5A2/LRH-1 bound to coregulatory nuclear responsive element (NRE) halfsites located in close proximity to FXREs modulate transcriptional activity (By similarity). In the liver activates transcription of the corepressor NR0B2 thereby indirectly inhibiting CYP7A1 and CYP8B1 (involved in BA synthesis) implicating at least in part histone demethylase KDM1A resulting in epigenomic repression, and SLC10A1/NTCP (involved in hepatic uptake of conjugated BAs). Activates transcription of the repressor MAFG (involved in regulation of BA synthesis) (By similarity). Activates transcription of SLC27A5/BACS and BAAT (involved in BA conjugation), ABCB11/BSEP (involved in bile salt export) by directly recruiting histone methyltransferase CARM1, and ABCC2/MRP2 (involved in secretion of conjugated BAs) and ABCB4 (involved in secretion of phosphatidylcholine in the small intestine) (PubMed:12754200, PubMed:15471871, PubMed:17895379). Activates transcription of SLC27A5/BACS and BAAT (involved in BA conjugation), ABCB11/BSEP (involved in bile salt export) by directly recruiting histone methyltransferase CARM1, and ABCC2/MRP2 (involved in secretion of conjugated BAs) and ABCB4 (involved in secretion of phosphatidylcholine in the small intestine) (PubMed:10514450, PubMed:15239098, PubMed:16269519). In the intestine activates FGF19 expression and secretion leading to hepatic CYP7A1 repression (PubMed:12815072, PubMed:19085950). The function also involves the coordinated induction of hepatic KLB/beta-klotho expression (By similarity). Regulates transcription of liver UGT2B4 and SULT2A1 involved in BA detoxification; binding to the UGT2B4 promoter seems to imply a monomeric transactivation independent of RXRA (PubMed:12806625, PubMed:16946559). Modulates lipid homeostasis by activating liver NR0B2/SHP-mediated repression of SREBF1 (involved in de novo lipogenesis), expression of PLTP (involved in HDL formation), SCARB1 (involved in HDL hepatic uptake), APOE, APOC1, APOC4, PPARA (involved in beta-oxidation of fatty acids), VLDLR and SDC1 (involved in the hepatic uptake of LDL and IDL remnants), and inhibiting expression of MTTP (involved in VLDL assembly (PubMed:12554753, PubMed:12660231, PubMed:15337761). Increases expression of APOC2 (promoting lipoprotein lipase activity implicated in triglyceride clearance) (PubMed:11579204). Transrepresses APOA1 involving a monomeric competition with NR2A1 for binding to a DR1 element (PubMed:11927623, PubMed:21804189). Also reduces triglyceride clearance by inhibiting expression of ANGPTL3 and APOC3 (both involved in inhibition of lipoprotein lipase) (PubMed:12891557). Involved in glucose homeostasis by modulating hepatic gluconeogenesis through activation of NR0B2/SHP-mediated repression of respective genes. Modulates glycogen synthesis (inducing phosphorylation of glycogen synthase kinase-3) (By similarity). Modulates glucose-stimulated insulin secretion and is involved in insulin resistance (PubMed:20447400). Involved in intestinal innate immunity. Plays a role in protecting the distal small intestine against bacterial overgrowth and preservation of the epithelial barrier (By similarity). Down-regulates inflammatory cytokine expression in several types of immune cells including macrophages and mononuclear cells (PubMed:21242261). Mediates trans-repression of TLR4-induced cytokine expression; the function seems to require its sumoylation and prevents N-CoR nuclear receptor corepressor clearance from target genes such as IL1B and NOS2 (PubMed:19864602). Involved in the TLR9-mediated protective mechanism in intestinal inflammation. Plays an anti-inflammatory role in liver inflammation; proposed to inhibit pro-inflammatory (but not antiapoptotic) NF-kappa-B signaling) (By similarity)
- Specific Function
- bile acid binding
- Gene Name
- NR1H4
- Uniprot ID
- Q96RI1
- Uniprot Name
- Bile acid receptor
- Molecular Weight
- 55913.915 Da
References
- Pellicciari R, Fiorucci S, Camaioni E, Clerici C, Costantino G, Maloney PR, Morelli A, Parks DJ, Willson TM: 6alpha-ethyl-chenodeoxycholic acid (6-ECDCA), a potent and selective FXR agonist endowed with anticholestatic activity. J Med Chem. 2002 Aug 15;45(17):3569-72. [Article]
- Eslam M, Alvani R, Shiha G: Obeticholic acid: towards first approval for NASH. Lancet. 2019 Dec 14;394(10215):2131-2133. doi: 10.1016/S0140-6736(19)32963-0. Epub 2019 Dec 5. [Article]
- Manne V, Kowdley KV: Obeticholic acid in primary biliary cholangitis: where we stand. Curr Opin Gastroenterol. 2019 May;35(3):191-196. doi: 10.1097/MOG.0000000000000525. [Article]
- Chianelli D, Rucker PV, Roland J, Tully DC, Nelson J, Liu X, Bursulaya B, Hernandez ED, Wu J, Prashad M, Schlama T, Liu Y, Chu A, Schmeits J, Huang DJ, Hill R, Bao D, Zoll J, Kim Y, Groessl T, McNamara P, Liu B, Richmond W, Sancho-Martinez I, Phimister A, Seidel HM, Badman MK, Joseph SB, Laffitte B, Molteni V: Nidufexor (LMB763), a Novel FXR Modulator for the Treatment of Nonalcoholic Steatohepatitis. J Med Chem. 2020 Apr 23;63(8):3868-3880. doi: 10.1021/acs.jmedchem.9b01621. Epub 2020 Feb 5. [Article]
- Luo G, Lin X, Li Z, Xiao M, Li X, Zhang D, Xiang H: Structure-guided modification of isoxazole-type FXR agonists: Identification of a potent and orally bioavailable FXR modulator. Eur J Med Chem. 2021 Jan 1;209:112910. doi: 10.1016/j.ejmech.2020.112910. Epub 2020 Oct 7. [Article]
- Hernandez ED, Zheng L, Kim Y, Fang B, Liu B, Valdez RA, Dietrich WF, Rucker PV, Chianelli D, Schmeits J, Bao D, Zoll J, Dubois C, Federe GC, Chen L, Joseph SB, Klickstein LB, Walker J, Molteni V, McNamara P, Meeusen S, Tully DC, Badman MK, Xu J, Laffitte B: Tropifexor-Mediated Abrogation of Steatohepatitis and Fibrosis Is Associated With the Antioxidative Gene Expression Profile in Rodents. Hepatol Commun. 2019 May 17;3(8):1085-1097. doi: 10.1002/hep4.1368. eCollection 2019 Aug. [Article]
- FDA Accepts Intercept’s NDA for OCA for the Treatment of Liver Fibrosis Due to NASH and Grants Priority Review [Link]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- InhibitorDownregulator
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, steroid hormones and vitamins (PubMed:10681376, PubMed:11555828, PubMed:12865317, PubMed:19965576, PubMed:9435160). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:10681376, PubMed:11555828, PubMed:12865317, PubMed:19965576, PubMed:9435160). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:11555828, PubMed:12865317). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2 (PubMed:11555828, PubMed:12865317). Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). May act as a major enzyme for all-trans retinoic acid biosynthesis in the liver. Catalyzes two successive oxidative transformation of all-trans retinol to all-trans retinal and then to the active form all-trans retinoic acid (PubMed:10681376). Primarily catalyzes stereoselective epoxidation of the last double bond of polyunsaturated fatty acids (PUFA), displaying a strong preference for the (R,S) stereoisomer (PubMed:19965576). Catalyzes bisallylic hydroxylation and omega-1 hydroxylation of PUFA (PubMed:9435160). May also participate in eicosanoids metabolism by converting hydroperoxide species into oxo metabolites (lipoxygenase-like reaction, NADPH-independent) (PubMed:21068195). Plays a role in the oxidative metabolism of xenobiotics. Catalyzes the N-hydroxylation of heterocyclic amines and the O-deethylation of phenacetin (PubMed:14725854). Metabolizes caffeine via N3-demethylation (Probable)
- Specific Function
- aromatase activity
- Gene Name
- CYP1A2
- Uniprot ID
- P05177
- Uniprot Name
- Cytochrome P450 1A2
- Molecular Weight
- 58406.915 Da
References
- Edwards JE, Eliot L, Parkinson A, Karan S, MacConell L: Assessment of Pharmacokinetic Interactions Between Obeticholic Acid and Caffeine, Midazolam, Warfarin, Dextromethorphan, Omeprazole, Rosuvastatin, and Digoxin in Phase 1 Studies in Healthy Subjects. Adv Ther. 2017 Sep;34(9):2120-2138. doi: 10.1007/s12325-017-0601-0. Epub 2017 Aug 14. [Article]
- Ishida C, Sanoh S, Kotake Y: CYP1A2 Downregulation by Obeticholic Acid: Usefulness as a Positive Control for the In Vitro Evaluation of Drug-Drug Interactions. J Pharm Sci. 2019 Dec;108(12):3903-3910. doi: 10.1016/j.xphs.2019.08.021. Epub 2019 Aug 28. [Article]
- FDA Approved Products: Ocaliva (obeticholic acid) oral tablets [Link]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- InhibitorInducer
- Curator comments
- This transporter action is not expected to result in clinically significant outcomes with obeticholic acid administered at a normal recommended dose.
- General Function
- Catalyzes the transport of the major hydrophobic bile salts, such as taurine and glycine-conjugated cholic acid across the canalicular membrane of hepatocytes in an ATP-dependent manner, therefore participates in hepatic bile acid homeostasis and consequently to lipid homeostasis through regulation of biliary lipid secretion in a bile salts dependent manner (PubMed:15791618, PubMed:16332456, PubMed:18985798, PubMed:19228692, PubMed:20010382, PubMed:20398791, PubMed:22262466, PubMed:24711118, PubMed:29507376, PubMed:32203132). Transports taurine-conjugated bile salts more rapidly than glycine-conjugated bile salts (PubMed:16332456). Also transports non-bile acid compounds, such as pravastatin and fexofenadine in an ATP-dependent manner and may be involved in their biliary excretion (PubMed:15901796, PubMed:18245269)
- Specific Function
- ABC-type bile acid transporter activity
- Gene Name
- ABCB11
- Uniprot ID
- O95342
- Uniprot Name
- Bile salt export pump
- Molecular Weight
- 146405.83 Da
References
- FDA Approved Products: Ocaliva (obeticholic acid) oral tablets [Link]
Drug created at November 18, 2007 18:29 / Updated at September 12, 2023 18:32