Details of the Drug

General Information of Drug (ID: DMD1QXW)

Drug Name
Ambrisentan
Synonyms
Letairis; Ambrisentan [INN]; Gilead brand of ambrisentan; BSF 208075; BSF208075; LU 208075; LU208075; BSF-208075; LU-208075; Benzenepropanoic acid, .alpha.-[(4,6-dimethyl-2-pyrimidinyl)oxy]-.beta.-methoxy-.beta.-phe; (+-)-(2S)-2-((4,6-Dimethylpyrimidin-2-yl)oxy)-3-methoxy-3,3-diphenylpropanoic acid; 2-(4,6-dimethylpyrimidin-2-yl)oxy-3-methoxy-3,3-diphenyl-propanoic acid; 2-(4,6-dimethylpyrimidin-2-yl)oxy-3-methoxy-3,3-diphenylpropanoic acid; 2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropanoic acid
Indication
Disease Entry ICD 11 Status REF
Pulmonary arterial hypertension BB01.0 Approved [1]
Drug Type
Small molecular drug
Structure
3D MOL 2D MOL
#Ro5 Violations (Lipinski): 0 Molecular Weight (mw) 378.4
Logarithm of the Partition Coefficient (xlogp) 3.8
Rotatable Bond Count (rotbonds) 7
Hydrogen Bond Donor Count (hbonddonor) 1
Hydrogen Bond Acceptor Count (hbondacc) 6
ADMET Property
Absorption Tmax
The time to maximum plasma concentration (Tmax) is 2 h []
BDDCS Class
Biopharmaceutics Drug Disposition Classification System (BDDCS) Class 1: high solubility and high permeability [2]
Clearance
The apparent oral clearance of drug is 38 mL/min []
Elimination
5% of drug is excreted from urine in the unchanged form [2]
Half-life
The concentration or amount of drug in body reduced by one-half in 15 hours [3]
Metabolism
The drug is metabolized via uridine 5-diphosphate glucuronosyltransferases (UGTs) 1A9S, 2B7S,1A3S to form ambrisentan glucuronide []
MRTD
The Maximum Recommended Therapeutic Dose (MRTD) of drug that ensured maximising efficacy and moderate side effect is 0.3795 micromolar/kg/day [4]
Water Solubility
The ability of drug to dissolve in water is measured as 0.06 mg/mL [2]
Chemical Identifiers
Formula
C22H22N2O4
IUPAC Name
(2S)-2-(4,6-dimethylpyrimidin-2-yl)oxy-3-methoxy-3,3-diphenylpropanoic acid
Canonical SMILES
CC1=CC(=NC(=N1)O[C@H](C(=O)O)C(C2=CC=CC=C2)(C3=CC=CC=C3)OC)C
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
InChIKey
OUJTZYPIHDYQMC-LJQANCHMSA-N
Cross-matching ID
PubChem CID
6918493
ChEBI ID
CHEBI:135949
CAS Number
177036-94-1
DrugBank ID
DB06403
TTD ID
D0X5ZI
VARIDT ID
DR00311
INTEDE ID
DR0080
ACDINA ID
D00028
Combinatorial Drugs (CBD) Click to Jump to the Detailed CBD Information of This Drug

Molecular Interaction Atlas of This Drug


Drug Therapeutic Target (DTT)
DTT Name DTT ID UniProt ID MOA REF
Endothelin A receptor (EDNRA) TTKRD0G EDNRA_HUMAN Antagonist [5]

Drug Transporter (DTP)
DTP Name DTP ID UniProt ID MOA REF
P-glycoprotein 1 (ABCB1) DTUGYRD MDR1_HUMAN Substrate [6]

Drug-Metabolizing Enzyme (DME)
DME Name DME ID UniProt ID MOA REF
Cytochrome P450 3A4 (CYP3A4) DE4LYSA CP3A4_HUMAN Substrate [7]
Mephenytoin 4-hydroxylase (CYP2C19) DEGTFWK CP2CJ_HUMAN Substrate [7]
UDP-glucuronosyltransferase 2B7 (UGT2B7)
Main DME 		DEB3CV1 UD2B7_HUMAN Substrate [7]
UDP-glucuronosyltransferase 1A9 (UGT1A9)
Main DME 		DE85D2P UD19_HUMAN Substrate [7]
UDP-glucuronosyltransferase 1A3 (UGT1A3)
Main DME 		DEF2WXN UD13_HUMAN Substrate [7]
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This Drug

Molecular Expression Atlas of This Drug

The Studied Disease Pulmonary arterial hypertension
ICD Disease Classification BB01.0
Molecule Name Molecule Type Gene Name p-value Fold-Change Z-score
Endothelin A receptor (EDNRA) DTT EDNRA 3.19E-05 -2.69 -1.71
P-glycoprotein 1 (ABCB1) DTP P-GP 2.55E-01 4.83E-01 5.66E-01
Mephenytoin 4-hydroxylase (CYP2C19) DME CYP2C19 1.39E-02 -2.78E-01 -5.67E-01
Cytochrome P450 3A4 (CYP3A4) DME CYP3A4 1.10E-01 -1.23E-01 -2.88E-01
Molecular Expression Atlas (MEA) Jump to Detail Molecular Expression Atlas of This Drug

Drug-Drug Interaction (DDI) Information of This Drug

Coadministration of a Drug Treating the Disease Different from Ambrisentan (Comorbidity)
DDI Drug Name DDI Drug ID Severity Mechanism Comorbidity REF
Midostaurin DMI6E0R Moderate Decreased clearance of Ambrisentan due to the transporter inhibition by Midostaurin. Acute myeloid leukaemia [2A60] [8]
Arn-509 DMT81LZ Moderate Increased metabolism of Ambrisentan caused by Arn-509 mediated induction of CYP450 enzyme. Acute myeloid leukaemia [2A60] [9]
Bedaquiline DM3906J Moderate Increased risk of hepatotoxicity by the combination of Ambrisentan and Bedaquiline. Antimicrobial drug resistance [MG50-MG52] [10]
Ag-221 DMS0ZBI Moderate Decreased clearance of Ambrisentan due to the transporter inhibition by Ag-221. BCR-ABL1-negative chronic myeloid leukaemia [2A41] [11]
Erdafitinib DMI782S Moderate Decreased clearance of Ambrisentan due to the transporter inhibition by Erdafitinib. Bladder cancer [2C94] [12]
Pexidartinib DMS2J0Z Major Increased risk of hepatotoxicity by the combination of Ambrisentan and Pexidartinib. Bone/articular cartilage neoplasm [2F7B] [13]
Tucatinib DMBESUA Minor Decreased metabolism of Ambrisentan caused by Tucatinib mediated inhibition of CYP450 enzyme. Breast cancer [2C60-2C6Y] [8]
PF-04449913 DMSB068 Moderate Decreased clearance of Ambrisentan due to the transporter inhibition by PF-04449913. Chronic myelomonocytic leukaemia [2A40] [9]
Ivacaftor DMZC1HS Moderate Decreased clearance of Ambrisentan due to the transporter inhibition by Ivacaftor. Cystic fibrosis [CA25] [14]
MK-8228 DMOB58Q Moderate Decreased clearance of Ambrisentan due to the transporter inhibition by MK-8228. Cytomegaloviral disease [1D82] [15]
Boceprevir DMBSHMF Minor Decreased metabolism of Ambrisentan caused by Boceprevir mediated inhibition of CYP450 enzyme. Hepatitis virus infection [1E50-1E51] [8]
Brentuximab vedotin DMWLC57 Moderate Increased risk of hepatotoxicity by the combination of Ambrisentan and Brentuximab vedotin. Hodgkin lymphoma [2B30] [16]
Fostemsavir DM50ILT Moderate Decreased clearance of Ambrisentan due to the transporter inhibition by Fostemsavir. Human immunodeficiency virus disease [1C60-1C62] [17]
Cobicistat DM6L4H2 Minor Decreased metabolism of Ambrisentan caused by Cobicistat mediated inhibition of CYP450 enzyme. Human immunodeficiency virus disease [1C60-1C62] [8]
Etravirine DMGV8QU Moderate Increased metabolism of Ambrisentan caused by Etravirine mediated induction of CYP450 enzyme. Human immunodeficiency virus disease [1C60-1C62] [18]
Bempedoic acid DM1CI9R Moderate Decreased clearance of Ambrisentan due to the transporter inhibition by Bempedoic acid. Hyper-lipoproteinaemia [5C80] [19]
Teriflunomide DMQ2FKJ Major Increased risk of hepatotoxicity by the combination of Ambrisentan and Teriflunomide. Hyper-lipoproteinaemia [5C80] [20]
BMS-201038 DMQTAGO Major Increased risk of hepatotoxicity by the combination of Ambrisentan and BMS-201038. Hyper-lipoproteinaemia [5C80] [21]
Ceritinib DMB920Z Minor Decreased metabolism of Ambrisentan caused by Ceritinib mediated inhibition of CYP450 enzyme. Lung cancer [2C25] [8]
PF-06463922 DMKM7EW Moderate Increased metabolism of Ambrisentan caused by PF-06463922 mediated induction of CYP450 enzyme. Lung cancer [2C25] [22]
Capmatinib DMYCXKL Moderate Decreased clearance of Ambrisentan due to the transporter inhibition by Capmatinib. Lung cancer [2C25] [23]
Calaspargase pegol DMQZBXI Moderate Increased risk of hepatotoxicity by the combination of Ambrisentan and Calaspargase pegol. Malignant haematopoietic neoplasm [2B33] [24]
Idelalisib DM602WT Moderate Increased risk of hepatotoxicity by the combination of Ambrisentan and Idelalisib. Mature B-cell leukaemia [2A82] [25]
Dabrafenib DMX6OE3 Moderate Increased metabolism of Ambrisentan caused by Dabrafenib mediated induction of CYP450 enzyme. Melanoma [2C30] [9]
Lasmiditan DMXLVDT Moderate Decreased clearance of Ambrisentan due to the transporter inhibition by Lasmiditan. Migraine [8A80] [26]
Lefamulin DME6G97 Moderate Decreased metabolism of Ambrisentan caused by Lefamulin mediated inhibition of CYP450 enzyme. Pneumonia [CA40] [27]
Lonafarnib DMGM2Z6 Minor Decreased metabolism of Ambrisentan caused by Lonafarnib mediated inhibition of CYP450 enzyme. Premature ageing appearance [LD2B] [8]
Enzalutamide DMGL19D Moderate Increased metabolism of Ambrisentan caused by Enzalutamide mediated induction of CYP450 enzyme. Prostate cancer [2C82] [28]
Darolutamide DMV7YFT Moderate Decreased clearance of Ambrisentan due to the transporter inhibition by Darolutamide. Prostate cancer [2C82] [9]
Armodafinil DMGB035 Minor Increased metabolism of Ambrisentan caused by Armodafinil mediated induction of CYP450 enzyme. Solid tumour/cancer [2A00-2F9Z] [29]
Fostamatinib DM6AUHV Moderate Decreased clearance of Ambrisentan due to the transporter inhibition by Fostamatinib. Thrombocytopenia [3B64] [30]
⏷ Show the Full List of 31 DDI Information of This Drug

Drug Inactive Ingredient(s) (DIG) and Formulation(s) of This Drug

DIG
DIG Name DIG ID PubChem CID Functional Classification
Allura red AC dye E00338 33258 Colorant
Carmellose sodium E00625 Not Available Disintegrant
Lactose monohydrate E00393 104938 Binding agent; Diluent; Dry powder inhaler carrier; Lyophilization aid
Magnesium stearate E00208 11177 lubricant
Polyethylene glycol 3350 E00652 Not Available Coating agent; Diluent; Ointment base; Plasticizing agent; Solvent; Suppository base; lubricant
Polyvinyl alcohol E00666 Not Available Coating agent; Emulsion stabilizing agent; Film/Membrane-forming agent
Soybean lecithin E00637 Not Available Other agent
Talc E00520 16211421 Anticaking agent; Diluent; Glidant; lubricant
Titanium dioxide E00322 26042 Coating agent; Colorant; Opacifying agent
⏷ Show the Full List of 9 Pharmaceutical Excipients of This Drug
Pharmaceutical Formulation
Formulation Name Drug Dosage Dosage Form Route
Ambrisentan 10 mg tablet 10 mg Oral Tablet Oral
Ambrisentan 5 mg tablet 5 mg Oral Tablet Oral
Jump to Detail Pharmaceutical Formulation Page of This Drug

References

1 URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 3951).
2 BDDCS applied to over 900 drugs
3 Trend Analysis of a Database of Intravenous Pharmacokinetic Parameters in Humans for 1352 Drug Compounds
4 Estimating the safe starting dose in phase I clinical trials and no observed effect level based on QSAR modeling of the human maximum recommended daily dose
5 Clinical pipeline report, company report or official report of GlaxoSmithKline (2009).
6 Potential for pharmacokinetic interactions between ambrisentan and cyclosporine. Clin Pharmacol Ther. 2010 Oct;88(4):513-20.
7 Clinical pharmacokinetics and drug-drug interactions of endothelin receptor antagonists in pulmonary arterial hypertension. J Clin Pharmacol. 2012 Dec;52(12):1784-805.
8 Product Information. Letairis (ambrisentan). Gilead Sciences, Foster City, CA.
9 Cerner Multum, Inc. "UK Summary of Product Characteristics.".
10 Product Information. Sirturo (bedaquiline). Janssen Pharmaceuticals, Titusville, NJ.
11 Cerner Multum, Inc. "Australian Product Information.".
12 Product Information. Balversa (erdafitinib). Janssen Products, LP, Horsham, PA.
13 Product Information. Turalio (pexidartinib). Daiichi Sankyo, Inc., Parsippany, NJ.
14 Product Information. Kalydeco (ivacaftor). Vertex Pharmaceuticals, Cambridge, MA.
15 Product Information. Prevymis (letermovir). Merck & Company Inc, Whitehouse Station, NJ.
16 Product Information. Adcetris (brentuximab vedotin). Seattle Genetics Inc, Bothell, WA.
17 Product Information. Rukobia (fostemsavir). ViiV Healthcare, Research Triangle Park, NC.
18 Product Information. Intelence (etravirine). Ortho Biotech Inc, Bridgewater, NJ.
19 Product Information. Nexletol (bempedoic acid). Esperion Therapeutics, Ann Arbor, MI.
20 Canadian Pharmacists Association.
21 Product Information. Juxtapid (lomitapide). Aegerion Pharmaceuticals Inc, Cambridge, MA.
22 Product Information. Lorbrena (lorlatinib). Pfizer U.S. Pharmaceuticals Group, New York, NY.
23 Product Information. Tabrecta (capmatinib). Novartis Pharmaceuticals, East Hanover, NJ.
24 Al-Nawakil C, Willems L, Mauprivez C, et.al "Successful treatment of l-asparaginase-induced severe acute hepatotoxicity using mitochondrial cofactors." Leuk Lymphoma 55 (2014): 1670-4. [PMID: 24090500]
25 Product Information. Zydelig (idelalisib). Gilead Sciences, Foster City, CA.
26 Product Information. Reyvow (lasmiditan). Lilly, Eli and Company, Indianapolis, IN.
27 Product Information. Fycompa (perampanel). Eisai Inc, Teaneck, NJ.
28 Benoist G, van Oort I, et al "Drug-drug interaction potential in men treated with enzalutamide: Mind the gap." Br J Clin Pharmacol 0 (2017): epub. [PMID: 28881501]
29 Doherty MM, Charman WN "The mucosa of the small intestine: how clinically relevant as an organ of drug metabolism?" Clin Pharmacokinet 41 (2002): 235-53. [PMID: 11978143]
30 Product Information. Tavalisse (fostamatinib). Rigel Pharmaceuticals, South San Francisco, CA.