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Identification
- Summary
Ambrisentan is a selective type A endothelin receptor antagonist used to treat primary pulmonary arterial hypertension and pulmonary arterial hypertension based on diagnostic classifications.
- Brand Names
- Letairis
- Generic Name
- Ambrisentan
- DrugBank Accession Number
- DB06403
- Background
Ambrisentan is an orally active selective type A endothelin receptor antagonist indicated for the treatment of pulmonary arterial hypertension. It is approved in Europe, Canada and the United States for use as a single agent to improve exercise ability and delay clinical worsening. In addition, it is approved in the United States for use in combination with tadalafil to reduce the risks of disease progression, hospitalization and to improve exercise ability. Studies establishing the efficacy of Ambrisentan included patients with both idiopathic or heritable pulmonary arterial hypertension and those with pulmonary arterial hypertension associated with connective tissue diseases. Patients studied displayed symptoms and etiologies predominantly of WHO Functional Class II-III. As an endothelin receptor antagonist, Ambrisentan prevents endogenous endothelin peptide from constricting the muscles in blood vessels, allowing them to relax and permit a reduction in blood pressure.
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Ambrisentan (DB06403)
- Weight
- Average: 378.428
Monoisotopic: 378.157957196 - Chemical Formula
- C22H22N2O4
- Synonyms
- (2S)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy- 3,3-diphenylpropanoic acid
- Ambrisentan
- External IDs
- BSF 208075
- BSF-208075
- BSF208075
- GSK-1325760
- GSK-1325760A
- GSK1325760
- GSK1325760A
- LU 208075
- LU-208075
- LU208075
Pharmacology
- Indication
Ambrisentan is indicated for treatment of idiopathic (‘primary’) pulmonary arterial hypertension (IPAH) and pulmonary arterial hypertension (PAH) associated with connective tissue disease in patients with WHO functional class II or III symptoms. In the United States of America, ambrisentan is also indicated in combination with tadalafil to reduce the risks of disease progression and hospitalization for worsening PAH, and to improve exercise ability.
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Management of Who group 1 pulmonary arterial hypertension •••••••••••• - 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
Ambrisentan 10 mg daily had no significant effect on the QTc interval, whereas a 40 mg daily dose of ambrisentan increased mean QTc at tmax by 5 ms with an upper 95% confidence limit of 9 ms. Significant QTc prolongation is not expected in patients taking ambrisentan without concomitant metabolic inhibitors. Plasma concentrations of B-type natriuretic peptide (BNP) in patients who received ambrisentan for 12 weeks were significantly decreased. Two Phase III placebo-controlled studies demonstrated a decrease in BNP plasma concentrations by 29% in the 2.5 mg group, 30% in the 5 mg group, and 45% in the 10 mg group (p < 0.001 for each dose group) and an increase by 11% in the placebo group.
- Mechanism of action
Endothelin-1 (ET-1) is an endogenous peptide that acts on the endothelin type A (ETA) and endothelin type B (ETB) receptors in vascular smooth muscle and endothelium. ETA-mediated actions include vasoconstriction and cell proliferation, whereas ETB predominantly mediates vasodilation, anti-proliferation, and ET-1 clearance. In patients with pulmonary arterial hypertension, ET-1 levels are increased and correlate with increased right arterial pressure and severity of disease. Ambrisentan is one of several newly developed vasodilator drugs that selectively target the endothelin type A (ETA) receptor, inhibiting its action and preventing vasoconstriction. Selective inhibition of the ETA receptor prevents phospholipase C-mediated vasoconstriction and protein kinase C-mediated cell proliferation. Endothelin type B (ETB) receptor function is not significantly inhibited, and nitric oxide and prostacyclin production, cyclic GMP- and cyclic AMP-mediated vasodilation, and endothelin-1 (ET-1) clearance is preserved.
Target Actions Organism AEndothelin-1 receptor antagonistHumans NEndothelin receptor type B antagonistHumans - Absorption
Ambrisentan is rapidly absorbed with peak plasma concentrations occuring around 2 hours after oral administration. Cmax and AUC increase proportionally with dose across the therapeutic dosing range. Absolute oral bioavailability of ambrisentan is unknown. Absorption is not affected by food.
- Volume of distribution
Ambrisentan has a low distribution into red blow cells, with a mean blood:plasma ratio of 0.57 and 0.61 in males and females, respectively.
- Protein binding
Ambrisentan is 99% plasma protein bound, primarily to albumin (96.5%) and to a lesser degree alpha1-acid glycoprotein.
- Metabolism
Ambrisentan is a metabolized primarily by uridine 5’-diphosphate glucuronosyltransferases (UGTs) 1A9S, 2B7S,1A3S to form ambrisentan glucuronide. Ambrisentan is also metabolized to a lesser extent by CYP3A4, CYP3A5 and CYP2C19 to form 4- hydroxymethyl ambrisentan which is further glucuronidated to 4-hydroxymethyl ambrisentan glucuronide.
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- Route of elimination
Ambrisentan is primarily cleared by non-renal pathways. Along with its metabolites, ambrisentan is primarily found in the feces following hepatic and/or extra-hepatic metabolism. Approximately 22% of the administered dose is recovered in the urine following oral administration with 3.3% being unchanged ambrisentan.
- Half-life
Ambrisentan has a terminal half-life of 15 hours. It is thought that steady state is achieved after around 4 days of repeat-dosing.
- Clearance
The mean oral clearance of ambrisentan was found to be 38 mL/min in healthy subjects and 19 mL/min in patients with pulmonary artery hypertension.
- 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
Ambrisentan is teratogenic and has a high risk of embryo-fetal toxicity. LD50 was found to be greater than or equal to 3160 mg/kg when studied in rats. There was no evidence of carcinogenic potential in 2 year oral daily dosing studies in rats and mice.
- 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 softwareAbaloparatide Abaloparatide may increase the hypotensive activities of Ambrisentan. Abametapir The serum concentration of Ambrisentan can be increased when it is combined with Abametapir. Abatacept The metabolism of Ambrisentan can be increased when combined with Abatacept. Abemaciclib The serum concentration of Abemaciclib can be increased when it is combined with Ambrisentan. Abrocitinib The serum concentration of Ambrisentan can be increased when it is combined with Abrocitinib. - Food Interactions
- No interactions found.
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
- Ambrican (Lupin) / Endobloc (Cipla Ltd.) / Pulmonext (MSN Labs) / Zambri (German Remedies Ltd.)
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Ambrisentan Mylan Tablet, film coated 10 mg Oral Mylan Pharmaceuticals Inc. 2020-12-16 Not applicable EU 
Ambrisentan Mylan Tablet, film coated 5 mg Oral Mylan Pharmaceuticals Inc. 2020-12-16 Not applicable EU Ambrisentan Mylan Tablet, film coated 10 mg Oral Mylan Pharmaceuticals Inc. 2020-12-16 Not applicable EU Ambrisentan Mylan Tablet, film coated 10 mg Oral Mylan Pharmaceuticals Inc. 2020-12-16 Not applicable EU Ambrisentan Mylan Tablet, film coated 5 mg Oral Mylan Pharmaceuticals Inc. 2020-12-16 Not applicable EU - Generic Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Ambrisentan Tablet, film coated 10 mg/1 Oral Quallent Pharmaceuticals Health LLC 2024-05-01 Not applicable US 
Ambrisentan Tablet, film coated 5 mg/1 Oral Zydus Pharmaceuticals USA Inc. 2019-04-12 Not applicable US Ambrisentan Tablet, film coated 10 mg/1 Oral Exelan Pharmaceuticals Inc. 2020-07-22 Not applicable US Ambrisentan Tablet, film coated 5 mg/1 Oral Actavis Pharma, Inc. 2019-04-30 Not applicable US Ambrisentan Tablet, film coated 10 mg/1 Oral Zydus Pharmaceuticals USA Inc. 2019-04-12 Not applicable US
Categories
- ATC Codes
- C02KX02 — Ambrisentan
- C02KX — Antihypertensives for pulmonary arterial hypertension
- C02K — OTHER ANTIHYPERTENSIVES
- C02 — ANTIHYPERTENSIVES
- C — CARDIOVASCULAR SYSTEM
- Drug Categories
- Acids, Carbocyclic
- Antihypertensive Agents
- Antihypertensives for Pulmonary Arterial Hypertension
- Cardiovascular Agents
- Cytochrome P-450 CYP2C19 Substrates
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 CYP3A5 Substrates
- Cytochrome P-450 Substrates
- Endothelin Receptor Antagonists
- Hypertension, Pulmonary
- OATP1B1/SLCO1B1 Substrates
- OATP1B3 substrates
- P-glycoprotein substrates
- UGT1A3 substrates
- UGT1A9 Substrates
- UGT2B7 substrates
- Vasodilating Agents
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as diphenylmethanes. These are compounds containing a diphenylmethane moiety, which consists of a methane wherein two hydrogen atoms are replaced by two phenyl groups.
- Kingdom
- Organic compounds
- Super Class
- Benzenoids
- Class
- Benzene and substituted derivatives
- Sub Class
- Diphenylmethanes
- Direct Parent
- Diphenylmethanes
- Alternative Parents
- Phenylpropanoic acids / Benzylethers / Alkyl aryl ethers / Pyrimidines and pyrimidine derivatives / Monosaccharides / Heteroaromatic compounds / Monocarboxylic acids and derivatives / Dialkyl ethers / Carboxylic acids / Azacyclic compounds show 5 more
- Substituents
- 3-phenylpropanoic-acid / Alkyl aryl ether / Aromatic heteromonocyclic compound / Azacycle / Benzylether / Carbonyl group / Carboxylic acid / Carboxylic acid derivative / Dialkyl ether / Diphenylmethane show 13 more
- Molecular Framework
- Aromatic heteromonocyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- HW6NV07QEC
- CAS number
- 177036-94-1
- InChI Key
- OUJTZYPIHDYQMC-LJQANCHMSA-N
- InChI
- InChI=1S/C22H22N2O4/c1-15-14-16(2)24-21(23-15)28-19(20(25)26)22(27-3,17-10-6-4-7-11-17)18-12-8-5-9-13-18/h4-14,19H,1-3H3,(H,25,26)/t19-/m1/s1
- IUPAC Name
- (2S)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropanoic acid
- SMILES
- COC([C@H](OC1=NC(C)=CC(C)=N1)C(O)=O)(C1=CC=CC=C1)C1=CC=CC=C1
References
- Synthesis Reference
- Riechers H, Albrecht HP, Amberg W, Baumann E, Bernard H, Bohm HJ, Klinge D, Kling A, Muller S, Raschack M, Unger L, Walker N, Wernet W: Discovery and optimization of a novel class of orally active nonpeptidic endothelin-A receptor antagonists. J Med Chem. 1996 May 24;39(11):2123-8. Pubmed.
- Peng X, Li P, Shi Y: Synthesis of (+)-ambrisentan via chiral ketone-catalyzed asymmetric epoxidation. J Org Chem. 2012 Jan 6;77(1):701-3. doi: 10.1021/jo201927m. Epub 2011 Nov 29. Pubmed.
- General References
- Said K: AMBITION: An important piece in the therapeutic puzzle of pulmonary arterial hypertension. Glob Cardiol Sci Pract. 2015 Nov 13;2015(4):48. doi: 10.5339/gcsp.2015.48. eCollection 2015. [Article]
- Markert C, Wirsching T, Hellwig R, Burhenne J, Weiss J, Riedel KD, Mikus G, Haefeli WE: Lack of a clinically significant interaction of grapefruit juice with ambrisentan and bosentan in healthy adults. Int J Clin Pharmacol Ther. 2014 Nov;52(11):957-64. doi: 10.5414/CP202164. [Article]
- Galie N, Olschewski H, Oudiz RJ, Torres F, Frost A, Ghofrani HA, Badesch DB, McGoon MD, McLaughlin VV, Roecker EB, Gerber MJ, Dufton C, Wiens BL, Rubin LJ: Ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2. Circulation. 2008 Jun 10;117(23):3010-9. doi: 10.1161/CIRCULATIONAHA.107.742510. Epub 2008 May 27. [Article]
- Venitz J, Zack J, Gillies H, Allard M, Regnault J, Dufton C: Clinical pharmacokinetics and drug-drug interactions of endothelin receptor antagonists in pulmonary arterial hypertension. J Clin Pharmacol. 2012 Dec;52(12):1784-805. doi: 10.1177/0091270011423662. Epub 2011 Dec 28. [Article]
- Peacock AJ, Zamboni W, Vizza CD: Ambrisentan for the treatment of adults with pulmonary arterial hypertension: a review. Curr Med Res Opin. 2015;31(9):1793-807. doi: 10.1185/03007995.2015.1074890. Epub 2015 Aug 27. [Article]
- Casserly B, Klinger JR: Ambrisentan for the treatment of pulmonary arterial hypertension. Drug Des Devel Ther. 2009 Feb 6;2:265-80. [Article]
- Kingman M, Ruggiero R, Torres F: Ambrisentan, an endothelin receptor type A-selective endothelin receptor antagonist, for the treatment of pulmonary arterial hypertension. Expert Opin Pharmacother. 2009 Aug;10(11):1847-58. doi: 10.1517/14656560903061275. [Article]
- Buckley MS, Wicks LM, Staib RL, Kirejczyk AK, Varker AS, Gibson JJ, Feldman JP: Pharmacokinetic evaluation of ambrisentan. Expert Opin Drug Metab Toxicol. 2011 Mar;7(3):371-80. doi: 10.1517/17425255.2011.557181. Epub 2011 Feb 8. [Article]
- External Links
- PubChem Compound
- 6918493
- PubChem Substance
- 310264868
- ChemSpider
- 5293690
- BindingDB
- 50146710
- 358274
- ChEBI
- 135949
- ChEMBL
- CHEMBL1111
- ZINC
- ZINC000000538627
- PharmGKB
- PA165860521
- RxList
- RxList Drug Page
- Drugs.com
- Drugs.com Drug Page
- PDRhealth
- PDRhealth Drug Page
- Wikipedia
- Ambrisentan
- FDA label
- Download (1.74 MB)
- MSDS
- Download (94.4 KB)
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 Pulmonary Arterial Hypertension (PAH) 1 somestatus stop reason just information to hide Not Available Completed Not Available Pulmonary Hypertension (PH) 2 somestatus stop reason just information to hide Not Available Completed Treatment Ischemia 1 somestatus stop reason just information to hide Not Available Completed Treatment Scleroderma, Systemic / Skin Ulcer 1 somestatus stop reason just information to hide Not Available Completed Treatment Scleroderma / Systemic Sclerosis (SSc) 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Powder Not applicable 1 kg/1kg Tablet, film coated Oral 10 mg/1 Tablet, film coated Oral 5 mg/1 Tablet, film coated Oral Tablet, film coated Oral 10 mg Tablet, film coated Oral 5 mg Tablet, coated Oral 10 mg Tablet, film coated Oral 500000 mg Tablet Oral 10 mg Tablet Oral 5 mg Tablet, film coated Oral 2.5 mg Tablet, film coated Oral 10.0 mg Tablet, film coated Oral 5.0 mg Tablet, coated Oral 5 mg - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US5703017 No 1997-12-30 2014-12-30 US CA2201785 No 2006-08-29 2015-10-07 Canada 
US5840722 No 1998-11-24 2015-11-24 US US7601730 No 2009-10-13 2015-10-07 US US8377933 No 2013-02-19 2027-12-11 US US7109205 No 2006-09-19 2015-10-07 US USRE42462 No 2011-06-14 2018-07-29 US US8349843 No 2013-01-08 2015-10-07 US US9474752 No 2016-10-25 2027-12-11 US US9549926 No 2017-01-24 2031-10-14 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source melting point (°C) 165-168 °C # Riechers H, Albrecht HP, Amberg W, Baumann E, Bernard H, Bohm HJ, Klinge D, Kling A, Muller S, Raschack M, Unger L, Walker N, Wernet W: Discovery and optimization of a novel class of orally active nonpeptidic endothelin-A receptor antagonists. J Med Chem. 1996 May 24;39(11):2123-8. "Pubmed":http://www.ncbi.nlm.nih.gov/pubmed/8667356 water solubility Ambrisentan is practically insoluble in aqueous solutions at low pH. Solubility increases at higher pH. # FDA Label pKa 4.0 # FDA Label - Predicted Properties
Property Value Source Water Solubility 0.05 mg/mL ALOGPS logP 3.9 ALOGPS logP 3.5 Chemaxon logS -3.9 ALOGPS pKa (Strongest Acidic) 3.59 Chemaxon pKa (Strongest Basic) 2.48 Chemaxon Physiological Charge -1 Chemaxon Hydrogen Acceptor Count 6 Chemaxon Hydrogen Donor Count 1 Chemaxon Polar Surface Area 81.54 Å2 Chemaxon Rotatable Bond Count 7 Chemaxon Refractivity 104.17 m3·mol-1 Chemaxon Polarizability 38.86 Å3 Chemaxon Number of Rings 3 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter Yes Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 199.9499013 predictedDarkChem Lite v0.1.0 [M-H]- 183.76973 predictedDeepCCS 1.0 (2019) [M+H]+ 200.2980013 predictedDarkChem Lite v0.1.0 [M+H]+ 186.1653 predictedDeepCCS 1.0 (2019) [M+Na]+ 200.4034013 predictedDarkChem Lite v0.1.0 [M+Na]+ 192.07782 predictedDeepCCS 1.0 (2019)
Targets
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- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Antagonist
- General Function
- Receptor for endothelin-1. Mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. The rank order of binding affinities for ET-A is: ET1 > ET2 >> ET3
- Specific Function
- endothelin receptor activity
- Gene Name
- EDNRA
- Uniprot ID
- P25101
- Uniprot Name
- Endothelin-1 receptor
- Molecular Weight
- 48721.76 Da
References
- Spence R, Mandagere A, Richards DB, Magee MH, Dufton C, Boinpally R: Potential for pharmacokinetic interactions between ambrisentan and cyclosporine. Clin Pharmacol Ther. 2010 Oct;88(4):513-20. doi: 10.1038/clpt.2010.120. Epub 2010 Sep 1. [Article]
- Richards DB, Walker GA, Mandagere A, Magee MH, Henderson LS: Effect of ketoconazole on the pharmacokinetic profile of ambrisentan. J Clin Pharmacol. 2009 Jun;49(6):719-24. doi: 10.1177/0091270009335870. Epub 2009 Apr 23. [Article]
- Kingman M, Ruggiero R, Torres F: Ambrisentan, an endothelin receptor type A-selective endothelin receptor antagonist, for the treatment of pulmonary arterial hypertension. Expert Opin Pharmacother. 2009 Aug;10(11):1847-58. doi: 10.1517/14656560903061275. [Article]
- Casserly B, Klinger JR: Ambrisentan for the treatment of pulmonary arterial hypertension. Drug Des Devel Ther. 2009 Feb 6;2:265-80. [Article]
- Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Antagonist
- General Function
- Non-specific receptor for endothelin 1, 2, and 3. Mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system
- Specific Function
- endothelin receptor activity
- Gene Name
- EDNRB
- Uniprot ID
- P24530
- Uniprot Name
- Endothelin receptor type B
- Molecular Weight
- 49643.255 Da
References
- Casserly B, Klinger JR: Ambrisentan for the treatment of pulmonary arterial hypertension. Drug Des Devel Ther. 2009 Feb 6;2:265-80. [Article]
- Kingman M, Ruggiero R, Torres F: Ambrisentan, an endothelin receptor type A-selective endothelin receptor antagonist, for the treatment of pulmonary arterial hypertension. Expert Opin Pharmacother. 2009 Aug;10(11):1847-58. doi: 10.1517/14656560903061275. [Article]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of sterols, steroid hormones, retinoids and fatty acids (PubMed:10681376, PubMed:11093772, PubMed:11555828, PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:19965576, PubMed:20702771, PubMed:21490593, PubMed:21576599). 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). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:21490593, PubMed:21576599, PubMed:2732228). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2, as well as D-ring hydroxylated E1 and E2 at the C-16 position (PubMed:11555828, PubMed:12865317, PubMed:14559847). Plays a role in the metabolism of androgens, particularly in oxidative deactivation of testosterone (PubMed:15373842, PubMed:15764715, PubMed:22773874, PubMed:2732228). Metabolizes testosterone to less biologically active 2beta- and 6beta-hydroxytestosterones (PubMed:15373842, PubMed:15764715, PubMed:2732228). Contributes to the formation of hydroxycholesterols (oxysterols), particularly A-ring hydroxylated cholesterol at the C-4beta position, and side chain hydroxylated cholesterol at the C-25 position, likely contributing to cholesterol degradation and bile acid biosynthesis (PubMed:21576599). Catalyzes bisallylic hydroxylation of polyunsaturated fatty acids (PUFA) (PubMed:9435160). Catalyzes the epoxidation of double bonds of PUFA with a preference for the last double bond (PubMed:19965576). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:20702771). Plays a role in the metabolism of retinoids. Displays high catalytic activity for oxidation of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes atRA toward 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Responsible for oxidative metabolism of xenobiotics. Acts as a 2-exo-monooxygenase for plant lipid 1,8-cineole (eucalyptol) (PubMed:11159812). Metabolizes the majority of the administered drugs. Catalyzes sulfoxidation of the anthelmintics albendazole and fenbendazole (PubMed:10759686). Hydroxylates antimalarial drug quinine (PubMed:8968357). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850). Also involved in vitamin D catabolism and calcium homeostasis. Catalyzes the inactivation of the active hormone calcitriol (1-alpha,25-dihydroxyvitamin D(3)) (PubMed:29461981)
- Specific Function
- 1,8-cineole 2-exo-monooxygenase activity
- Gene Name
- CYP3A4
- Uniprot ID
- P08684
- Uniprot Name
- Cytochrome P450 3A4
- Molecular Weight
- 57342.67 Da
References
- Spence R, Mandagere A, Richards DB, Magee MH, Dufton C, Boinpally R: Potential for pharmacokinetic interactions between ambrisentan and cyclosporine. Clin Pharmacol Ther. 2010 Oct;88(4):513-20. doi: 10.1038/clpt.2010.120. Epub 2010 Sep 1. [Article]
- Richards DB, Walker GA, Mandagere A, Magee MH, Henderson LS: Effect of ketoconazole on the pharmacokinetic profile of ambrisentan. J Clin Pharmacol. 2009 Jun;49(6):719-24. doi: 10.1177/0091270009335870. Epub 2009 Apr 23. [Article]
- Venitz J, Zack J, Gillies H, Allard M, Regnault J, Dufton C: Clinical pharmacokinetics and drug-drug interactions of endothelin receptor antagonists in pulmonary arterial hypertension. J Clin Pharmacol. 2012 Dec;52(12):1784-805. doi: 10.1177/0091270011423662. Epub 2011 Dec 28. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of polyunsaturated fatty acids (PUFA) (PubMed:18577768, PubMed:19965576, PubMed:20972997). 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:18577768, PubMed:19965576, PubMed:20972997). Catalyzes the hydroxylation of carbon-hydrogen bonds. Hydroxylates PUFA specifically at the omega-1 position (PubMed:18577768). Catalyzes the epoxidation of double bonds of PUFA (PubMed:19965576, PubMed:20972997). Also metabolizes plant monoterpenes such as limonene. Oxygenates (R)- and (S)-limonene to produce carveol and perillyl alcohol (PubMed:11950794). Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and imipramine. Hydroxylates fenbendazole at the 4' position (PubMed:23959307)
- Specific Function
- (R)-limonene 6-monooxygenase activity
- Gene Name
- CYP2C19
- Uniprot ID
- P33261
- Uniprot Name
- Cytochrome P450 2C19
- Molecular Weight
- 55944.565 Da
References
- Buckley MS, Wicks LM, Staib RL, Kirejczyk AK, Varker AS, Gibson JJ, Feldman JP: Pharmacokinetic evaluation of ambrisentan. Expert Opin Drug Metab Toxicol. 2011 Mar;7(3):371-80. doi: 10.1517/17425255.2011.557181. Epub 2011 Feb 8. [Article]
- Venitz J, Zack J, Gillies H, Allard M, Regnault J, Dufton C: Clinical pharmacokinetics and drug-drug interactions of endothelin receptor antagonists in pulmonary arterial hypertension. J Clin Pharmacol. 2012 Dec;52(12):1784-805. doi: 10.1177/0091270011423662. Epub 2011 Dec 28. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- UDP-glucuronosyltransferase (UGT) that catalyzes phase II biotransformation reactions in which lipophilic substrates are conjugated with glucuronic acid to increase the metabolite's water solubility, thereby facilitating excretion into either the urine or bile (PubMed:12181437, PubMed:15470161, PubMed:15472229, PubMed:18004212, PubMed:18052087, PubMed:18674515, PubMed:19545173). Essential for the elimination and detoxification of drugs, xenobiotics and endogenous compounds (PubMed:12181437, PubMed:18004212). Catalyzes the glucuronidation of endogenous estrogen hormones such as estradiol and estrone (PubMed:15472229). Also catalyzes the glucuronidation of the isoflavones genistein, daidzein, glycitein, formononetin, biochanin A and prunetin, which are phytoestrogens with anticancer and cardiovascular properties (PubMed:18052087, PubMed:19545173). Involved in the glucuronidation of the AGTR1 angiotensin receptor antagonist caderastan, a drug which can inhibit the effect of angiotensin II (PubMed:18674515). Involved in the biotransformation of 7-ethyl-10-hydroxycamptothecin (SN-38), the pharmacologically active metabolite of the anticancer drug irinotecan (PubMed:12181437, PubMed:20610558). Also metabolizes mycophenolate, an immunosuppressive agent (PubMed:15470161, PubMed:18004212)
- Specific Function
- enzyme binding
- Gene Name
- UGT1A9
- Uniprot ID
- O60656
- Uniprot Name
- UDP-glucuronosyltransferase 1A9
- Molecular Weight
- 59940.495 Da
References
- Buckley MS, Wicks LM, Staib RL, Kirejczyk AK, Varker AS, Gibson JJ, Feldman JP: Pharmacokinetic evaluation of ambrisentan. Expert Opin Drug Metab Toxicol. 2011 Mar;7(3):371-80. doi: 10.1517/17425255.2011.557181. Epub 2011 Feb 8. [Article]
- Venitz J, Zack J, Gillies H, Allard M, Regnault J, Dufton C: Clinical pharmacokinetics and drug-drug interactions of endothelin receptor antagonists in pulmonary arterial hypertension. J Clin Pharmacol. 2012 Dec;52(12):1784-805. doi: 10.1177/0091270011423662. Epub 2011 Dec 28. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- UDP-glucuronosyltransferase (UGT) that catalyzes phase II biotransformation reactions in which lipophilic substrates are conjugated with glucuronic acid to increase the metabolite's water solubility, thereby facilitating excretion into either the urine or bile (PubMed:10702251, PubMed:15470161, PubMed:15472229, PubMed:17442341, PubMed:18674515, PubMed:18719240, PubMed:19022937, PubMed:23288867, PubMed:23756265, PubMed:26220143). Essential for the elimination and detoxification of drugs, xenobiotics and endogenous compounds (PubMed:15470161, PubMed:18674515, PubMed:23756265). Catalyzes the glucuronidation of endogenous steroid hormones such as androgens (epitestosterone, androsterone) and estrogens (estradiol, epiestradiol, estriol, catechol estrogens) (PubMed:15472229, PubMed:17442341, PubMed:18719240, PubMed:19022937, PubMed:2159463, PubMed:23288867, PubMed:26220143). Also regulates the levels of retinoic acid, a major metabolite of vitamin A involved in apoptosis, cellular growth and differentiation, and embryonic development (PubMed:10702251). Contributes to bile acid (BA) detoxification by catalyzing the glucuronidation of BA substrates, which are natural detergents for dietary lipids absorption (PubMed:23756265). Involved in the glucuronidation of the AGTR1 angiotensin receptor antagonist losartan, caderastan and zolarsatan, drugs which can inhibit the effect of angiotensin II (PubMed:18674515). Also metabolizes mycophenolate, an immunosuppressive agent (PubMed:15470161)
- Specific Function
- glucuronosyltransferase activity
- Gene Name
- UGT2B7
- Uniprot ID
- P16662
- Uniprot Name
- UDP-glucuronosyltransferase 2B7
- Molecular Weight
- 60720.15 Da
References
- Buckley MS, Wicks LM, Staib RL, Kirejczyk AK, Varker AS, Gibson JJ, Feldman JP: Pharmacokinetic evaluation of ambrisentan. Expert Opin Drug Metab Toxicol. 2011 Mar;7(3):371-80. doi: 10.1517/17425255.2011.557181. Epub 2011 Feb 8. [Article]
- Venitz J, Zack J, Gillies H, Allard M, Regnault J, Dufton C: Clinical pharmacokinetics and drug-drug interactions of endothelin receptor antagonists in pulmonary arterial hypertension. J Clin Pharmacol. 2012 Dec;52(12):1784-805. doi: 10.1177/0091270011423662. Epub 2011 Dec 28. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- UDP-glucuronosyltransferase (UGT) that catalyzes phase II biotransformation reactions in which lipophilic substrates are conjugated with glucuronic acid to increase the metabolite's water solubility, thereby facilitating excretion into either the urine or bile (PubMed:15472229, PubMed:18674515, PubMed:18719240, PubMed:23288867, PubMed:23756265, PubMed:24641623). Essential for the elimination and detoxification of drugs, xenobiotics and endogenous compounds (PubMed:23756265). Catalyzes the glucuronidation of endogenous estrogen hormones such as estradiol and estrone (PubMed:15472229, PubMed:18719240, PubMed:23288867). Contributes to bile acid (BA) detoxification by catalyzing the glucuronidation of BA substrates, which are natural detergents for dietary lipids absorption (PubMed:23756265). Involved in the glucuronidation of calcidiol, which is the major circulating form of vitamin D3, essential for the regulation of calcium and phosphate homeostasis (PubMed:24641623). Involved in the glucuronidation of the AGTR1 angiotensin receptor antagonists losartan, candesartan and zolarsartan, which can inhibit the effect of angiotensin II (PubMed:18674515)
- Specific Function
- enzyme binding
- Gene Name
- UGT1A3
- Uniprot ID
- P35503
- Uniprot Name
- UDP-glucuronosyltransferase 1A3
- Molecular Weight
- 60337.835 Da
References
- Buckley MS, Wicks LM, Staib RL, Kirejczyk AK, Varker AS, Gibson JJ, Feldman JP: Pharmacokinetic evaluation of ambrisentan. Expert Opin Drug Metab Toxicol. 2011 Mar;7(3):371-80. doi: 10.1517/17425255.2011.557181. Epub 2011 Feb 8. [Article]
- Venitz J, Zack J, Gillies H, Allard M, Regnault J, Dufton C: Clinical pharmacokinetics and drug-drug interactions of endothelin receptor antagonists in pulmonary arterial hypertension. J Clin Pharmacol. 2012 Dec;52(12):1784-805. doi: 10.1177/0091270011423662. Epub 2011 Dec 28. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of steroid hormones and vitamins (PubMed:10681376, PubMed:11093772, PubMed:12865317, PubMed:2732228). 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). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:10681376, PubMed:11093772, PubMed:12865317, PubMed:2732228). Exhibits high catalytic activity for the formation of catechol estrogens from 17beta-estradiol (E2) and estrone (E1), namely 2-hydroxy E1 and E2 (PubMed:12865317). Catalyzes 6beta-hydroxylation of the steroid hormones testosterone, progesterone, and androstenedione (PubMed:2732228). Catalyzes the oxidative conversion of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes all trans-retinoic acid (atRA) to 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Also involved in the oxidative metabolism of xenobiotics, including calcium channel blocking drug nifedipine and immunosuppressive drug cyclosporine (PubMed:2732228)
- Specific Function
- aromatase activity
- Gene Name
- CYP3A5
- Uniprot ID
- P20815
- Uniprot Name
- Cytochrome P450 3A5
- Molecular Weight
- 57108.065 Da
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Translocates drugs and phospholipids across the membrane (PubMed:2897240, PubMed:35970996, PubMed:8898203, PubMed:9038218). Catalyzes the flop of phospholipids from the cytoplasmic to the exoplasmic leaflet of the apical membrane. Participates mainly to the flop of phosphatidylcholine, phosphatidylethanolamine, beta-D-glucosylceramides and sphingomyelins (PubMed:8898203). Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells (PubMed:2897240, PubMed:35970996, PubMed:9038218)
- Specific Function
- ABC-type xenobiotic transporter activity
- Gene Name
- ABCB1
- Uniprot ID
- P08183
- Uniprot Name
- ATP-dependent translocase ABCB1
- Molecular Weight
- 141477.255 Da
References
- Venitz J, Zack J, Gillies H, Allard M, Regnault J, Dufton C: Clinical pharmacokinetics and drug-drug interactions of endothelin receptor antagonists in pulmonary arterial hypertension. J Clin Pharmacol. 2012 Dec;52(12):1784-805. doi: 10.1177/0091270011423662. Epub 2011 Dec 28. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Mediates the Na(+)-independent uptake of organic anions (PubMed:10358072, PubMed:15159445, PubMed:17412826). Shows broad substrate specificity, can transport both organic anions such as bile acid taurocholate (cholyltaurine) and conjugated steroids (dehydroepiandrosterone 3-sulfate, 17-beta-glucuronosyl estradiol, and estrone 3-sulfate), as well as eicosanoids (prostaglandin E2, thromboxane B2, leukotriene C4, and leukotriene E4), and thyroid hormones (T4/L-thyroxine, and T3/3,3',5'-triiodo-L-thyronine) (PubMed:10358072, PubMed:10601278, PubMed:10873595, PubMed:11159893, PubMed:12196548, PubMed:12568656, PubMed:15159445, PubMed:15970799, PubMed:16627748, PubMed:17412826, PubMed:19129463, PubMed:26979622). Can take up bilirubin glucuronides from plasma into the liver, contributing to the detoxification-enhancing liver-blood shuttling loop (PubMed:22232210). Involved in the clearance of endogenous and exogenous substrates from the liver (PubMed:10358072, PubMed:10601278). Transports coproporphyrin I and III, by-products of heme synthesis, and may be involved in their hepatic disposition (PubMed:26383540). May contribute to regulate the transport of organic compounds in testes across the blood-testis-barrier (Probable). Can transport HMG-CoA reductase inhibitors (also known as statins), such as pravastatin and pitavastatin, a clinically important class of hypolipidemic drugs (PubMed:10601278, PubMed:15159445, PubMed:15970799). May play an important role in plasma and tissue distribution of the structurally diverse chemotherapeutic drug methotrexate (PubMed:23243220). May also transport antihypertension agents, such as the angiotensin-converting enzyme (ACE) inhibitor prodrug enalapril, and the highly selective angiotensin II AT1-receptor antagonist valsartan, in the liver (PubMed:16624871, PubMed:16627748). Shows a pH-sensitive substrate specificity towards prostaglandin E2 and T4 which may be ascribed to the protonation state of the binding site and leads to a stimulation of substrate transport in an acidic microenvironment (PubMed:19129463). Hydrogencarbonate/HCO3(-) acts as the probable counteranion that exchanges for organic anions (PubMed:19129463)
- Specific Function
- bile acid transmembrane transporter activity
- Gene Name
- SLCO1B1
- Uniprot ID
- Q9Y6L6
- Uniprot Name
- Solute carrier organic anion transporter family member 1B1
- Molecular Weight
- 76447.99 Da
References
- Venitz J, Zack J, Gillies H, Allard M, Regnault J, Dufton C: Clinical pharmacokinetics and drug-drug interactions of endothelin receptor antagonists in pulmonary arterial hypertension. J Clin Pharmacol. 2012 Dec;52(12):1784-805. doi: 10.1177/0091270011423662. Epub 2011 Dec 28. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Mediates the Na(+)-independent uptake of organic anions (PubMed:10779507, PubMed:15159445, PubMed:17412826). Shows broad substrate specificity, can transport both organic anions such as bile acid taurocholate (cholyltaurine) and conjugated steroids (17-beta-glucuronosyl estradiol, dehydroepiandrosterone sulfate (DHEAS), and estrone 3-sulfate), as well as eicosanoid leukotriene C4, prostaglandin E2 and L-thyroxine (T4) (PubMed:10779507, PubMed:11159893, PubMed:12568656, PubMed:15159445, PubMed:17412826, PubMed:19129463). Hydrogencarbonate/HCO3(-) acts as the probable counteranion that exchanges for organic anions (PubMed:19129463). Shows a pH-sensitive substrate specificity towards sulfated steroids, taurocholate and T4 which may be ascribed to the protonation state of the binding site and leads to a stimulation of substrate transport in an acidic microenvironment (PubMed:19129463). Involved in the clearance of bile acids and organic anions from the liver (PubMed:22232210). Can take up bilirubin glucuronides from plasma into the liver, contributing to the detoxification-enhancing liver-blood shuttling loop (PubMed:22232210). Transports coproporphyrin I and III, by-products of heme synthesis, and may be involved in their hepatic disposition (PubMed:26383540). May contribute to regulate the transport of organic compounds in testes across the blood-testis-barrier (Probable). Can transport HMG-CoA reductase inhibitors (also known as statins) such as pitavastatin, a clinically important class of hypolipidemic drugs (PubMed:15159445). May play an important role in plasma and tissue distribution of the structurally diverse chemotherapeutic drugs methotrexate and paclitaxel (PubMed:23243220). May also transport antihypertension agents, such as the angiotensin-converting enzyme (ACE) inhibitor prodrug enalapril, and the highly selective angiotensin II AT1-receptor antagonist valsartan, in the liver (PubMed:16624871, PubMed:16627748)
- Specific Function
- bile acid transmembrane transporter activity
- Gene Name
- SLCO1B3
- Uniprot ID
- Q9NPD5
- Uniprot Name
- Solute carrier organic anion transporter family member 1B3
- Molecular Weight
- 77402.175 Da
References
- Venitz J, Zack J, Gillies H, Allard M, Regnault J, Dufton C: Clinical pharmacokinetics and drug-drug interactions of endothelin receptor antagonists in pulmonary arterial hypertension. J Clin Pharmacol. 2012 Dec;52(12):1784-805. doi: 10.1177/0091270011423662. Epub 2011 Dec 28. [Article]
Drug created at March 19, 2008 16:29 / Updated at October 17, 2024 13:59