Chemical: Drug
busulfan

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


Annotated Labels

  1. FDA Label for busulfan and ABL1,BCR
  2. EMA Label for busulfan

last updated 10/25/2013

1. FDA Label for busulfan and ABL1,BCR

Actionable PGx

Summary

The busulfan FDA-approved drug label states it is less effective in patients with chronic myelogenous leukemia who lack the Philadelphia (Ph1) chromosome. Testing for the BCR-ABL1 gene fusion is not mentioned in the drug label.

Annotation

Busulfan (Myleran) is indicated for palliative treatment of patients with chronic myelogenous leukemia. It is less effective in patients who lack the Philadelphia chromosome (BCR-ABL1 gene fusion).

Excerpt from the busulfan drug label:

Busulfan is clearly less effective in patients with chronic myelogenous leukemia who lack the Philadelphia (Ph1) chromosome. Also, the so-called "juvenile" type of chronic myelogenous leukemia, typically occurring in young children and associated with the absence of a Philadelphia chromosome, responds poorly to busulfan.

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Busulfan drug label.

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

Genes and/or phenotypes found in this label


last updated 05/29/2014

2. EMA Label for busulfan

Annotation

No pharmacogenetic information could be found in the EMA European Public Assessment Report (EPAR) for Busulfan (Busilvex): Dec 2012.


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

To see more Clinical Variants with lower levels of criteria, click the button at the bottom of the page.

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

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.

List of all variant annotations for busulfan

Gene ? Variant?
(147)
Alternate Names ? Chemicals ? Alleles ?
(+ chr strand)
Function ? Amino Acid?
Translation
No VIP available No VIP available VA CYP2B6 *1 N/A N/A N/A
No VIP available No VIP available VA CYP2B6 *5 N/A N/A N/A
No VIP available No VIP available VA CYP2B6 *9 N/A N/A N/A
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
No VIP available No Clinical Annotations available VA
rs1050152 NC_000005.10:g.132340627C>T, NC_000005.9:g.131676320C>T, NG_012129.1:g.51176C>T, NM_003059.2:c.1507C>T, NP_003050.2:p.Leu503Phe, NR_037898.1:n.560-5701G>A, NR_110997.1:n.561-5701G>A, XM_006714675.2:c.979C>T, XM_011543589.1:c.1231C>T, XP_006714738.1:p.Leu327Phe, XP_011541891.1:p.Leu411Phe, rs17680807, rs52829495, rs57045625
C > T
SNP
L503F
No VIP available CA VA
rs12248560 NC_000010.10:g.96521657C>T, NC_000010.11:g.94761900C>T, NG_008384.2:g.4195C>T, NM_000769.2:c.-806C>T, rs117093607, rs17442305, rs17879736
C > A
C > T
SNP
No VIP available CA VA
rs1799853 NC_000010.10:g.96702047C=, NC_000010.10:g.96702047C>T, NC_000010.11:g.94942290C=, NC_000010.11:g.94942290C>T, NG_008385.1:g.8633C=, NG_008385.1:g.8633C>T, NM_000771.3:c.430C=, NM_000771.3:c.430C>T, NP_000762.2:p.Arg144=, NP_000762.2:p.Arg144Cys, XM_005269575.1:c.430C=, XM_005269575.1:c.430C>T, XP_005269632.1:p.Arg144=, XP_005269632.1:p.Arg144Cys, rs17110268, rs28371674, rs33968134, rs60690363
C > T
SNP
R144C
No VIP available No Clinical Annotations available VA
rs1801133 NC_000001.10:g.11856378G>A, NC_000001.11:g.11796321G>A, NG_013351.1:g.14783C>T, NM_005957.4:c.665C>T, NP_005948.3:p.Ala222Val, XM_005263458.1:c.788C>T, XM_005263458.2:c.788C>T, XM_005263459.1:c.734C>T, XM_005263460.1:c.665C>T, XM_005263460.3:c.665C>T, XM_005263461.1:c.665C>T, XM_005263461.3:c.665C>T, XM_005263462.1:c.665C>T, XM_005263462.3:c.665C>T, XM_005263463.1:c.419C>T, XM_005263463.2:c.419C>T, XM_011541495.1:c.785C>T, XM_011541496.1:c.788C>T, XP_005263515.1:p.Ala263Val, XP_005263516.1:p.Ala245Val, XP_005263517.1:p.Ala222Val, XP_005263518.1:p.Ala222Val, XP_005263519.1:p.Ala222Val, XP_005263520.1:p.Ala140Val, XP_011539797.1:p.Ala262Val, XP_011539798.1:p.Ala263Val, rs386545618, rs4134713, rs59514310
G > A
SNP
A222V
No VIP available CA VA
rs3754446 NC_000001.10:g.110253241A>C, NC_000001.11:g.109710619A>C, NM_000851.3:c.-1694A>C, XM_005270784.1:c.-1229A>C, XM_005270784.3:c.-1229A>C, rs386585508, rs59602189
A > C
SNP
No VIP available No Clinical Annotations available VA
rs3957356 NC_000006.11:g.52668670T>C, NC_000006.12:g.52803872T>C, NM_001319059.1:c.-264A>G, NM_145740.4:c.-118A>G, XM_005249034.1:c.-118A>G, XM_005249034.2:c.-118A>G, rs59071523
T > C
SNP
No VIP available CA VA
rs3957357 NC_000006.11:g.52668687A>G, NC_000006.12:g.52803889A>G, NM_001319059.1:c.-281T>C, NM_145740.4:c.-135T>C, XM_005249034.1:c.-135T>C, XM_005249034.2:c.-135T>C, rs58145964
A > G
SNP
No VIP available No Clinical Annotations available VA
rs4148405 NC_000017.10:g.48713568T>G, NC_000017.11:g.50636207T>G, NM_001144070.1:c.45+1226T>G, NM_003786.3:c.45+1226T>G, XM_005257763.1:c.45+1226T>G, XM_005257763.2:c.45+1226T>G, XM_011525422.1:c.45+1226T>G, XM_011525423.1:c.45+1226T>G, XR_934586.1:n.138+1226T>G
T > G
SNP
No VIP available No Clinical Annotations available VA
rs4715354 NC_000006.11:g.52708797G>A, NC_000006.12:g.52843999G>A, NM_153699.1:c.-31+2057C>T, rs17268789, rs58826387
G > A
SNP
No VIP available No Clinical Annotations available VA
rs7141505 NC_000014.8:g.23653188C>A, NC_000014.9:g.23183979C>A, NM_012244.3:c.-1065G>T, XM_011536313.1:c.-1590C>A, XM_011536314.1:c.-1590C>A, XM_011536315.1:c.-1590C>A, XM_011536316.1:c.-1590C>A, XM_011536317.1:c.-1590C>A, XM_011536318.1:c.-1590C>A, XM_011536322.1:c.-1590C>A, XM_011536323.1:c.-1590C>A, XM_011536324.1:c.-1590C>A, XM_011536325.1:c.-1590C>A, XM_011536326.1:c.-1590C>A, XM_011536327.1:c.-1590C>A, XM_011536329.1:c.-1590C>A, XM_011536330.1:c.-1590C>A, XM_011536331.1:c.-1590C>A, XM_011536332.1:c.-1590C>A, XM_011536333.1:c.-1590C>A, XM_011536335.1:c.-1590C>A, XR_943355.1:n.-1355C>A, rs58253342
C > A
SNP
No VIP available No Clinical Annotations available VA
rs7746993 NC_000006.11:g.52714137C>A, NC_000006.12:g.52849339C>A, NG_029175.2:g.21120G>T, rs59957668
C > A
SNP
Alleles, Functions, and Amino Acid Translations are all sourced from dbSNP 147

Overview

Generic Names
  • Busulphan
  • Busulphane
  • Butanedioldimethanesulfonate
  • Buzulfan
  • Sulfabutin
  • Sulphabutin
  • Tetramethylene Dimethane Sulfonate
  • Tetramethylenester Kyseliny Methansulfonove
  • busulfan
Trade Names
  • Busilvex
  • Busulfex
  • Citosulfan
  • Leucosulfan
  • Mablin
  • Mielevcin
  • Mielosan
  • Mielucin
  • Milecitan
  • Mileran
  • Misulban
  • Mitosan
  • Mitostan
  • Myeleukon
  • Myeloleukon
  • Myelosan
  • Mylecytan
  • Myleran
  • Myleran Tablets
Brand Mixture Names

PharmGKB Accession Id

PA448691

Type(s):

Drug

Description

An alkylating agent having a selective immunosuppressive effect on bone marrow. It has been used in the palliative treatment of chronic myeloid leukemia (myeloid leukemia, chronic), but although symptomatic relief is provided, no permanent remission is brought about. According to the Fourth Annual Report on Carcinogens (NTP 85-002, 1985), busulfan is listed as a known carcinogen.

Source: Drug Bank

Indication

For use in combination with cyclophosphamide as a conditioning regimen prior to allogeneic hematopoietic progenitor cell transplantation for chronic myelogenous leukemia (FDA has designated busulfan as an orphan drug for this use). Also used as a component of pretransplant conditioning regimens in patients undergoing bone marrow transplantation for acute myeloid leukemia and nonmalignant diseases.

Source: Drug Bank

Other Vocabularies

Information pulled from DrugBank has not been reviewed by PharmGKB.

Pharmacology, Interactions, and Contraindications

Mechanism of Action

Busulfan is an alkylating agent that contains 2 labile methanesulfonate groups attached to opposite ends of a 4-carbon alkyl chain. Once busulfan is hydrolyzed, the methanesulfonate groups are released and carbonium ions are produced. These carbonium ions alkylate DNA, which results in the interference of DNA replication and RNA transcription, ultimately leading to the disruption of nucleic acid function. Specifically, its mechanism of action through alkylation produces guanine-adenine intrastrand crosslinks. This occurs through an SN2 reaction in which the relatively nucleophilic guanine N7 attacks the carbon adjacent to the mesylate leaving group. This kind of damage cannot be repaired by cellular machinery and thus the cell undergoes apoptosis.

Source: Drug Bank

Pharmacology

Busulfan is an antineoplastic in the class of alkylating agents and is used to treat various forms of cancer. Alkylating agents are so named because of their ability to add alkyl groups to many electronegative groups under conditions present in cells. They stop tumor growth by cross-linking guanine bases in DNA double-helix strands - directly attacking DNA. This makes the strands unable to uncoil and separate. As this is necessary in DNA replication, the cells can no longer divide. In addition, these drugs add methyl or other alkyl groups onto molecules where they do not belong which in turn leads to a miscoding of DNA. Alkylating agents are cell cycle-nonspecific and work by three different mechanisms, all of which achieve the same end result - disruption of DNA function and cell death.

Source: Drug Bank

Food Interaction

Drink liberally.|Take without regard to meals.

Source: Drug Bank

Absorption, Distribution, Metabolism, Elimination & Toxicity

Biotransformation

Mainly Hepatic. Busulfan is predominantly metabolized by conjugation with glutathione, both spontaneously and by glutathione S-transferase (GST) catalysis.

Source: Drug Bank

Protein Binding

32.4%

Source: Drug Bank

Absorption

Completely absorbed from the gastrointestinal tract.

Source: Drug Bank

Half-Life

2.5 hours

Source: Drug Bank

Toxicity

Signs of overdose include allergic reaction, unusual bleeding or bruising, sudden weakness or unusual fatigue, persistent cough, congestion, or shortness of breath; flank, stomach or joint pain; pronounced nausea, vomiting, diarrhea, dizziness, confusion, or darkening of the skin, chills, fever, collapse, and loss of consciousness.

Source: Drug Bank

Route of Elimination

Following administration of 14C- labeled busulfan to humans, approximately 30% of the radioactivity was excreted into the urine over 48 hours; negligible amounts were recovered in feces.

Source: Drug Bank

Chemical Properties

Chemical Formula

C6H14O6S2

Source: Drug Bank

Isomeric SMILES

CS(=O)(=O)OCCCCOS(=O)(=O)C

Source: OpenEye

Canonical SMILES

CS(=O)(=O)OCCCCOS(C)(=O)=O

Source: Drug Bank

Average Molecular Weight

246.302

Source: Drug Bank

Monoisotopic Molecular Weight

246.02317956

Source: Drug Bank

SMILES

CS(=O)(=O)OCCCCOS(C)(=O)=O

Source: Drug Bank

InChI String

InChI=1S/C6H14O6S2/c1-13(7,8)11-5-3-4-6-12-14(2,9)10/h3-6H2,1-2H3

Source: Drug Bank

PharmGKB Curated Pathways

Pathways created internally by PharmGKB based primarily on literature evidence.

External Pathways

Links to non-PharmGKB pathways.

PharmGKB contains no links to external pathways for this drug. To report a pathway, click here.

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 ?

Drug Interactions

Interaction Description
busulfan - metronidazole Metronidazole increases the effect/toxicity of busulfan (source: Drug Bank)
busulfan - metronidazole Metronidazole increases the effect/toxicity of busulfan (source: Drug Bank)
metronidazole - busulfan Metronidazole increases the effect/toxicity of busulfan (source: Drug Bank)
metronidazole - busulfan Metronidazole increases the effect/toxicity of busulfan (source: Drug Bank)
telithromycin - busulfan Telithromycin may reduce clearance of Busulfan. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Busulfan if Telithromycin is initiated, discontinued or dose changed. (source: Drug Bank)
thioguanine - busulfan Busulfan increases the hepatoxicity of Thioguanine during long-term concomitant therapy. (source: Drug Bank)
trastuzumab - busulfan Trastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events. (source: Drug Bank)
voriconazole - busulfan Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of busulfan by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of busulfan if voriconazole is initiated, discontinued or dose changed. (source: Drug Bank)

Curated Information ?

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

May Treat
Contraindicated With

Publications related to busulfan: 25

No Dosing Guideline available No Drug Label available No Clinical Annotation available VA No VIP available No VIP available
Population pharmacokinetics and pharmacodynamics of busulfan with GSTA1 polymorphisms in patients undergoing allogeneic hematopoietic stem cell transplantation. Pharmacogenomics. 2015. Choi Boyoon, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available VA No VIP available No VIP available
Exploratory analysis of 1936 SNPs in ADME genes for association with busulfan clearance in adult hematopoietic stem cell recipients. Pharmacogenetics and genomics. 2013. Ten Brink Marloes H, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Effect of genetic variants GSTA1 and CYP39A1 and age on busulfan clearance in pediatric patients undergoing hematopoietic stem cell transplantation. Pharmacogenomics. 2013. Ten Brink Marloes H, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
The association of cytochrome P450 genetic polymorphisms with sulfolane formation and the efficacy of a busulfan-based conditioning regimen in pediatric patients undergoing hematopoietic stem cell transplantation. The pharmacogenomics journal. 2013. Uppugunduri C R S, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Impact of polymorphisms in drug pathway genes on disease-free survival in adults with acute myeloid leukemia. Journal of human genetics. 2013. Yee Sook Wah, 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
Role of pharmacogenetics in busulfan/cyclophosphamide conditioning therapy prior to hematopoietic stem cell transplantation. Pharmacogenomics. 2013. Hassan Moustapha, 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
Pharmacogenomic characterization of US FDA-approved cytotoxic drugs. Pharmacogenomics. 2011. Peters Eric J, 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
Influence of GST Gene Polymorphisms on the Clearance of Intravenous Busulfan in Adult Patients Undergoing Hematopoietic Cell Transplantation. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2011. Kim Sung-Doo, 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
Systematic review of pharmacoeconomic studies of pharmacogenomic tests. Pharmacogenomics. 2010. Beaulieu Mathieu, 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
5-Aza-2'-deoxycytidine sensitizes busulfan-resistant myeloid leukemia cells by regulating expression of genes involved in cell cycle checkpoint and apoptosis. Leukemia research. 2010. Valdez Benigno C, 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
Impairment of APE1 function enhances cellular sensitivity to clinically relevant alkylators and antimetabolites. Molecular cancer research : MCR. 2009. McNeill Daniel R, 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
Altered gene expression in busulfan-resistant human myeloid leukemia. Leukemia research. 2008. Valdez Benigno C, 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
Metabolism of the cysteine S-conjugate of busulfan involves a beta-lyase reaction. Drug metabolism and disposition: the biological fate of chemicals. 2008. Cooper Arthur J L, 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
Elevated plasma ferritin and busulfan pharmacodynamics during high-dose chemotherapy regimens in children with malignant solid tumors. Clinical pharmacology and therapeutics. 2007. Bouligand J, 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
Overexpression of glutathione-S-transferase, MGSTII, confers resistance to busulfan and melphalan. Cancer investigation. 2005. Harkey Michael A, 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
Glutathione S-transferase M1 polymorphism: a risk factor for hepatic venoocclusive disease in bone marrow transplantation. Blood. 2004. Srivastava Alok, 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
DNA intrastrand cross-link at the 5'-GA-3' sequence formed by busulfan and its role in the cytotoxic effect. Cancer science. 2004. Iwamoto Takuya, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available VA No VIP available No VIP available
Predictors of oral mucositis in patients receiving hematopoietic cell transplants for chronic myelogenous leukemia. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2004. Robien Kim, 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
Genetic polymorphisms of glutathione S-transferase A1, the major glutathione S-transferase in human liver: consequences for enzyme expression and busulfan conjugation. Clinical pharmacology and therapeutics. 2002. Bredschneider Monika, 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
Hepsulfam induced DNA adducts and its excision repair by bacterial and mammalian 3-methyladenine DNA glycosylases. Molecules and cells. 1998. Je K H, 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
Busulfan conjugation by glutathione S-transferases alpha, mu, and pi. Drug metabolism and disposition: the biological fate of chemicals. 1996. Czerwinski M, 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
Busulfan-glutathione conjugation catalyzed by human liver cytosolic glutathione S-transferases. Cancer research. 1996. Gibbs J P, 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
The glutathione S-transferase supergene family: regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance. Critical reviews in biochemistry and molecular biology. 1995. Hayes J D, 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
Role of glutathione in cellular resistance to alkylating agents. Advances in enzyme regulation. 1993. Colvin O M, 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
Urinary metabolites of busulfan in the rat. Drug metabolism and disposition: the biological fate of chemicals. 1987. Hassan M, et al. PubMed

LinkOuts

Web Resource:
Wikipedia
National Drug Code Directory:
67286-0054-2
DrugBank:
DB01008
ChEBI:
28901
KEGG Drug:
D00248
PubChem Compound:
2478
PubChem Substance:
148760
46506234
Drugs Product Database (DPD):
2240602
ChemSpider:
2384
FDA Drug Label at DailyMed:
03dc50f9-c7bd-4c0c-8bbb-c1216ec90c95

Clinical Trials

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

No trials found.

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Sources for PharmGKB drug information: DrugBank, PubChem.