Drug/Small Molecule:
bosentan

PharmGKB contains no dosing guidelines for this drug/small molecule. To report known genotype-based dosing guidelines, or if you are interested in developing guidelines, click here.

PharmGKB has no annotated drug labels with pharmacogenomic information for this drug/small molecule. If you know of a drug label with PGx, send us a message.

PharmGKB contains no Clinical Variants that meet the highest level of criteria.

Disclaimer: The PharmGKB's clinical annotations reflect expert consensus based on clinical evidence and peer-reviewed literature available at the time they are written and are intended only to assist clinicians in decision-making and to identify questions for further research. New evidence may have emerged since the time an annotation was submitted to the PharmGKB. The annotations are limited in scope and are not applicable to interventions or diseases that are not specifically identified.

The annotations do not account for individual variations among patients, and cannot be considered inclusive of all proper methods of care or exclusive of other treatments. It remains the responsibility of the health-care provider to determine the best course of treatment for a patient. Adherence to any guideline is voluntary, with the ultimate determination regarding its application to be made solely by the clinician and the patient. PharmGKB assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of the PharmGKB clinical annotations, or for any errors or omissions.

? = Mouse-over for quick help

This is a non-comprehensive list of genetic tests with pharmacogenetics relevance, typically submitted by the manufacturer and manually curated by PharmGKB. The information listed is provided for educational purposes only and does not constitute an endorsement of any listed test or manufacturer.

A more complete listing of genetic tests is found at the Genetic Testing Registry (GTR).

PGx Test Variants Assayed Gene?

The table below contains information about pharmacogenomic variants on PharmGKB. Please follow the link in the "Variant" column for more information about a particular variant. Each link in the "Variant" column leads to the corresponding PharmGKB Variant Page. The Variant Page contains summary data, including PharmGKB manually curated information about variant-drug pairs based on individual PubMed publications. The PMIDs for these PubMed publications can be found on the Variant Page.

The tags in the first column of the table indicate what type of information can be found on the corresponding Variant Page.

Links in the "Gene" column lead to PharmGKB Gene Pages.

Gene ? Variant?
(138)
Alternate Names / Tag SNPs ? Drugs ? Alleles ?
(+ chr strand)
Function ? Amino Acid?
Translation
No VIP available No VIP available VA CYP2C9 *1 N/A N/A N/A
No VIP available No VIP available VA CYP2C9 *2 N/A N/A N/A
No VIP available No VIP available VA CYP2C9 *3 N/A N/A N/A
VIP No Clinical Annotations available No Variant Annotations available
rs2306283 14089862A>G, 21329738A>G, 388A>G, 50611A>G, Asn130Asp, SLCO1B1*1B
A > G
Missense
Asn130Asp
VIP No Clinical Annotations available No Variant Annotations available
rs4149015 -910G>A, 14043446G>A, 21283322G>A, 4195G>A, SLCO1B1:11187G>A, SLCO1B1:G-11187A
G > A
5' Flanking
VIP No Clinical Annotations available No Variant Annotations available
rs4149056 14091673T>C, 21331549T>C, 521T>C, 52422T>C, SLCO1B1*5, Val174Ala
T > C
Missense
Val174Ala
Alleles, Functions, and Amino Acid Translations are all sourced from dbSNP 138
2D structure from PubChem
provided by PubChem

Overview

Generic Names
  • Bosentan hydrate
  • bosentan
Trade Names
  • Tracleer
Brand Mixture Names

PharmGKB Accession Id:
PA10034

Description

Bosentan is a dual endothelin receptor antagonist important in the treatment of pulmonary artery hypertension (PAH). It is licensed in the United States, the European Union and other countries by Actelion Pharmaceuticals for the management of PAH under the trade name Tracleer R . Bosentan is used to treat pulmonary hypertension by blocking the action of endothelin molecules that would otherwise promote narrowing of the blood vessels and lead to high blood pressure.

Source: Drug Bank

Indication

Used in the treatment of pulmonary arterial hypertension (PAH), to improve exercise ability and to decrease the rate of clinical worsening (in patients with WHO Class III or IV symptoms).

Source: Drug Bank

Other Vocabularies

Information pulled from DrugBank has not been reviewed by PharmGKB.

Pharmacology, Interactions, and Contraindications

Mechanism of Action

Endothelin-1 (ET-1) is a neurohormone, the effects of which are mediated by binding to ET A and ET B receptors in the endothelium and vascular smooth muscle. ET-1 concentrations are elevated in plasma and lung tissue of patients with pulmonary arterial hypertension, suggesting a pathogenic role for ET-1 in this disease. Bosentan is a specific and competitive antagonist at endothelin receptor types ET A and ET B. Bosentan has a slightly higher affinity for ET A receptors than for ET B receptors.

Source: Drug Bank

Pharmacology

Bosentan belongs to a class of drugs known as endothelin receptor antagonists (ERAs). Patients with PAH have elevated levels of endothelin, a potent blood vessel constrictor, in their plasma and lung tissue. Bosentan blocks the binding of endothelin to its receptors, thereby negating endothelin's deleterious effects.

Source: Drug Bank

Food Interaction

Take without regard to meals.

Source: Drug Bank

Absorption, Distribution, Metabolism, Elimination & Toxicity

Biotransformation

Bosentan is metabolized in the liver by the cytochrome P450 enzymes CYP2C9 and CYP3A4 (and possibly CYP2C19), producing three metabolites, one of which, Ro 48-5033, is pharmacologically active and may contribute 10 to 20% to the total activity of the parent compound.

Source: Drug Bank

Protein Binding

Greater than 98% to plasma proteins, mainly albumin.

Source: Drug Bank

Absorption

Absolute bioavailability is approximately 50% and food does not affect absorption.

Source: Drug Bank

Half-Life

Terminal elimination half-life is about 5 hours in healthy adult subjects.

Source: Drug Bank

Toxicity

Bosentan has been given as a single dose of up to 2400 mg in normal volunteers, or up to 2000 mg/day for 2 months in patients, without any major clinical consequences. The most common side effect was headache of mild to moderate intensity. In the cyclosporine A interaction study, in which doses of 500 and 1000 mg b.i.d. of bosentan were given concomitantly with cyclosporine A, trough plasma concentrations of bosentan increased 30-fold, resulting in severe headache, nausea, and vomiting, but no serious adverse events. Mild decreases in blood pressure and increases in heart rate were observed. There is no specific experience of overdosage with bosentan beyond the doses described above. Massive overdosage may result in pronounced hypotension requiring active cardiovascular support.

Source: Drug Bank

Clearance

Route of Elimination

Bosentan is eliminated by biliary excretion following metabolism in the liver.

Source: Drug Bank

Volume of Distribution

  • 18 L

Source: Drug Bank

Chemical Properties

Chemical Formula

C27H29N5O6S

Source: Drug Bank

Isomeric SMILES

CC(C)(C)C1=CC=C(C=C1)S(=O)(=O)NC2=C(C(=NC(=N2)C3=NC=CC=N3)OCCO)OC4=CC=CC=C4OC

Source: Drug Bank

COC1=C(OC2=C(OCCO)N=C(N=C2NS(=O)(=O)C2=CC=C(C=C2)C(C)(C)C)C2=NC=CC=N2)C=CC=C1

Source: Drug Bank

Canonical SMILES

COC1=CC=CC=C1OC1=C(NS(=O)(=O)C2=CC=C(C=C2)C(C)(C)C)N=C(N=C1OCCO)C1=NC=CC=N1

Source: Drug Bank

Average Molecular Weight

551.614

Source: Drug Bank

Monoisotopic Molecular Weight

551.183854375

Source: Drug Bank

Genes that are associated with this drug in PharmGKB's database based on (1) variant annotations, (2) literature review, (3) pathways or (4) information automatically retrieved from DrugBank, depending on the "evidence" and "source" listed below.

Curated Information ?

EvidenceGene
No Dosing Guideline available No Drug Label available No Clinical Annotation available VA No VIP available No VIP available
CYP2C9
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available VIP No VIP available
NR1I2
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available VIP No VIP available
SLCO1B1

Drug Targets

Gene Description
ABCB11 (source: Drug Bank)
EDNRA (source: Drug Bank)
EDNRB (source: Drug Bank)

Drug Interactions

Drug Description
bosentan Bosentan could decrease atorvastatin (source: Drug Bank)
bosentan Bosentan could decrease atorvastatin (source: Drug Bank)
acenocoumarol Increases the anticoagulant effect (source: Drug Bank)
acenocoumarol Bosentan may decrease the anticoagulant effect of acenocoumarol by increasing its metabolism. (source: Drug Bank)
anisindione Bosentan may decrease the anticoagulant effect of anisindione by increasing its metabolism. (source: Drug Bank)
atorvastatin Bosentan could decrease atorvastatin effect (source: Drug Bank)
atorvastatin Bosentan could decrease atorvastatin effect (source: Drug Bank)
cerivastatin Bosentan could decrease the statin effect (source: Drug Bank)
cerivastatin Bosentan could decrease the statin effect (source: Drug Bank)
cyclosporine Cyclosporine increases the effect and toxicity of bosentan (source: Drug Bank)
cyclosporine Cyclosporine increases the effect and toxicity of bosentan (source: Drug Bank)
dicumarol Increase the anticoagulant effect (source: Drug Bank)
dicumarol Bosentan may decrease the anticoagulant effect of dicumarol by increasing its metabolism. (source: Drug Bank)
ethinyl estradiol Decreases the effect of contraceptive (source: Drug Bank)
glibenclamide Increased risk of hepatic toxicity (source: Drug Bank)
glibenclamide Increased risk of hepatic toxicity (source: Drug Bank)
itraconazole This imidazole increases the effect and toxicity of bosentan (source: Drug Bank)
itraconazole This imidazole increases the effect and toxicity of bosentan (source: Drug Bank)
ketoconazole This imidazole increases the effect and toxicity of bosentan (source: Drug Bank)
ketoconazole This imidazole increases the effect and toxicity of bosentan (source: Drug Bank)
lovastatin Bosentan could decrease the statin effect (source: Drug Bank)
lovastatin Bosentan could decrease the statin effect (source: Drug Bank)
medroxyprogesterone Decreases the effect of contraceptive (source: Drug Bank)
medroxyprogesterone Decreases the effect of contraceptive (source: Drug Bank)
mestranol Decreases the effect of contraceptive (source: Drug Bank)
mestranol Decreases the effect of contraceptive (source: Drug Bank)
norethindrone Decreases the effect of contraceptive (source: Drug Bank)
norethindrone Decreases the effect of contraceptive (source: Drug Bank)
simvastatin Bosentan could decrease the statin effect (source: Drug Bank)
simvastatin Bosentan could decrease the statin effect (source: Drug Bank)
voriconazole This imidazole increases the effect and toxicity of bosentan (source: Drug Bank)
voriconazole This imidazole increases the effect and toxicity of bosentan (source: Drug Bank)
warfarin Increases the anticoagulant effect (source: Drug Bank)
warfarin Bosentan may decrease the anticoagulant effect of warfarin by increasing its metabolism. (source: Drug Bank)
bosentan Bosentan could decrease the statin effect (source: Drug Bank)
bosentan Bosentan could decrease the statin effect (source: Drug Bank)
bosentan Increases the effect and toxicity of bosentan (source: Drug Bank)
bosentan Increases the effect and toxicity of bosentan (source: Drug Bank)
bosentan Bosentan decreases the effect of contraceptive (source: Drug Bank)
bosentan Bosentan decreases the effect of contraceptive (source: Drug Bank)
bosentan Increased risk of hepatic toxicity (source: Drug Bank)
bosentan Increased risk of hepatic toxicity (source: Drug Bank)
bosentan The imidazole increases the effect and toxicity of bosentan (source: Drug Bank)
bosentan The imidazole increases the effect and toxicity of bosentan (source: Drug Bank)
bosentan The imidazole increases the effect and toxicity of bosentan (source: Drug Bank)
bosentan The imidazole increases the effect and toxicity of bosentan (source: Drug Bank)
bosentan Bosentan could decrease the statin effect (source: Drug Bank)
bosentan Bosentan could decrease the statin effect (source: Drug Bank)
bosentan Bosentan decreases the effect of contraceptive (source: Drug Bank)
bosentan Bosentan decreases the effect of contraceptive (source: Drug Bank)
bosentan Bosentan decreases the effect of the contraceptive (source: Drug Bank)
bosentan Bosentan decreases the effect of the contraceptive (source: Drug Bank)
bosentan Co-administration may cause decreased Telithromycin and increased Bosentan plasma concentrations. Consider alternate therapy. (source: Drug Bank)
bosentan Bosentan may increase the metabolism of Temsirolimus decreasing its efficacy. Concomitant therapy should be avoided. (source: Drug Bank)
bosentan Tolbutamide, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of Bosentan. Consider alternate therapy or monitor for changes in Bosentan therapeutic and adverse effects if Tolbutamide is initiated, discontinued or dose changed. (source: Drug Bank)
bosentan Tolbutamide, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of Bosentan. Consider alternate therapy or monitor for changes in Bosentan therapeutic and adverse effects if Tolbutamide is initiated, discontinued or dose changed. (source: Drug Bank)
bosentan Bosentan may decrease the effect of Tramadol by increasing Tramadol metabolism and clearance. (source: Drug Bank)
bosentan The CYP3A4 inducer, Bosentan, may decrease Trazodone efficacy by increasing Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Bosentan is initiated, discontinued or dose changed. (source: Drug Bank)
bosentan The CYP3A4 inducer, Bosentan, may decrease Trazodone efficacy by increasing Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Bosentan is initiated, discontinued or dose changed. (source: Drug Bank)
bosentan Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of bosentan by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of bosentan if voriconazole is initiated, discontinued or dose changed. (source: Drug Bank)

Curated Information ?

EvidenceDisease
No Dosing Guideline available No Drug Label available No Clinical Annotation available VA No VIP available No VIP available
drug-induced liver injury

Relationships from National Drug File - Reference Terminology (NDF-RT)

May Treat
Contraindicated With

Publications related to bosentan: 9

No Dosing Guideline available No Drug Label available No Clinical Annotation available VA No VIP available No VIP available
CYP2C9 Polymorphism is not a Major Determinant of Bosentan Exposure in Healthy Volunteers. Clinical pharmacology and therapeutics. 2014. Markert C, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available VA No VIP available No VIP available
Association of CYP2C9*2 With Bosentan-Induced Liver Injury. Clinical pharmacology and therapeutics. 2013. Markova S M, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available VIP No VIP available
PharmGKB very important pharmacogene: SLCO1B1. Pharmacogenetics and genomics. 2010. Oshiro Connie, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Medicinal Chemistry of Drugs used in Diabetic Cardiomyopathy. Current medicinal chemistry. 2009. Adeghate E, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Xenobiotic transporters of the human organic anion transporting polypeptides (OATP) family. Xenobiotica; the fate of foreign compounds in biological systems. 2008. Hagenbuch B, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available VIP No VIP available
Bosentan is a substrate of human OATP1B1 and OATP1B3: inhibition of hepatic uptake as the common mechanism of its interactions with cyclosporin A, rifampicin, and sildenafil. Drug metabolism and disposition: the biological fate of chemicals. 2007. Treiber Alexander, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Inhibitory and inductive effects of rifampin on the pharmacokinetics of bosentan in healthy subjects. Clinical pharmacology and therapeutics. 2007. van Giersbergen P L M, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available VIP No VIP available
Investigation of the mutual pharmacokinetic interactions between bosentan, a dual endothelin receptor antagonist, and simvastatin. Clinical pharmacokinetics. 2003. Dingemanse Jasper, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available VIP No VIP available
Bosentan, a dual endothelin receptor antagonist, activates the pregnane X nuclear receptor. European journal of pharmacology. 2002. van Giersbergen Paul L M, et al. PubMed

LinkOuts

Web Resource:
Wikipedia
National Drug Code Directory:
66215-101-06
DrugBank:
DB00559
ChEBI:
51450
KEGG Drug:
D01227
PubChem Compound:
104865
PubChem Substance:
46507154
682323
Drugs Product Database (DPD):
2244982
ChemSpider:
94651
Therapeutic Targets Database:
DNC000341
FDA Drug Label at DailyMed:
749e42fb-2fe0-45dd-9268-b43bb3f4081c

Clinical Trials

These are trials that mention bosentan and are related to either pharmacogenetics or pharmacogenomics.

Common Searches

Search PubMed
Search Medline Plus
Search PubChem
Search CTD

Sources for PharmGKB drug information: DrugBank, Open Eye Scientific Software.