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Identification
NameBusulfan
Accession NumberDB01008  (APRD00664)
TypeSmall Molecule
GroupsApproved, Investigational
Description

Busulfan is a bifunctional alkylating agent, having a selective immunosuppressive effect on bone marrow. It is not a structural analog of the nitrogen mustards. 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. [PubChem]

Structure
Thumb
Synonyms
1,4-Bis(methanesulfonoxy)butane
1,4-Butanediol dimethanesulfonate
1,4-Dimesyloxybutane
1,4-Dimethanesulfonoxybutane
Bisulfex
Busulfan
Busulfano
Busulfanum
Leucosulfan
Mablin
Mielucin
Misulban
Mitostan
Myeloleukon
Myleran
Tetramethylene bis(methanesulfonate)
External Identifiers Not Available
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Busulfexinjection6 mg/mLintravenousOtsuka America Pharmaceutical, Inc.1999-02-04Not applicableUs
Busulfexinjection6 mg/mLintravenousOtsuka America Pharmaceutical, Inc.2015-02-13Not applicableUs
Busulfexsolution6 mgintravenousOtsuka Pharmaceutical Co Ltd1999-09-23Not applicableCanada
Mylerantablet2 mgoralAspen Pharma Trading Limited1954-12-31Not applicableCanada
Mylerantablet, film coated2 mg/1oralAspen Global Inc.1985-03-21Not applicableUs
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
BusilvexPierre Fabre
Brand mixturesNot Available
SaltsNot Available
Categories
UNIIG1LN9045DK
CAS number55-98-1
WeightAverage: 246.302
Monoisotopic: 246.02317956
Chemical FormulaC6H14O6S2
InChI KeyInChIKey=COVZYZSDYWQREU-UHFFFAOYSA-N
InChI
InChI=1S/C6H14O6S2/c1-13(7,8)11-5-3-4-6-12-14(2,9)10/h3-6H2,1-2H3
IUPAC Name
4-(methanesulfonyloxy)butyl methanesulfonate
SMILES
CS(=O)(=O)OCCCCOS(C)(=O)=O
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as methanesulfonates. These are compounds containing a methanesulfonate moiety, which consists of a methane linked to the sulfur atom of a sulfonate group.
KingdomOrganic compounds
Super ClassOrganic acids and derivatives
ClassSulfonic acids and derivatives
Sub ClassAlkanesulfonic acids and derivatives
Direct ParentMethanesulfonates
Alternative Parents
Substituents
  • Sulfonyl
  • Methanesulfonate
  • Hydrocarbon derivative
  • Organosulfur compound
  • Organooxygen compound
  • Aliphatic acyclic compound
Molecular FrameworkAliphatic acyclic compounds
External Descriptors
Pharmacology
IndicationFor use in combination with cyclophosphamide as a conditioning regimen prior to allogeneic hematopoietic progenitor cell transplantation for chronic myelogenous (myeloid, myelocytic, granulocytic) leukemia (FDA has designated busulfan as an orphan drug for this use). It is also used as a component of pretransplant conditioning regimens in patients undergoing bone marrow transplantation for acute myeloid leukemia and nonmalignant diseases.
PharmacodynamicsBusulfan 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. Overexpression of MGST2, a glutathione s-transferase, is thought to confer resistance to busulfan. The role of MGST2 in the metabolism of busulfan is unknown however.
Mechanism of actionBusulfan 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.
Related Articles
AbsorptionCompletely absorbed from the gastrointestinal tract. Busulfan is a small, highly lipophilic molecule that crosses the blood-brain-barrier. The absolute bioavailability, if a single 2 mg IV bolus injection is given to adult patients, is 80% ± 20%. In children (1.5 - 6 years old), the absolute bioavailability was 68% ± 31%. When a single oral dose is given to patients, the area under the curve (AUC) was 130 ng•hr/mL. The peak plasma concentration when given orally is 30 ng/mL (after dose normalization to 2 mg). It takes 0.9 hours to reach peak plasma concentration after dose normalization to 4 mg.
Volume of distributionNot Available
Protein binding32% bound to plasma proteins and 47% bound to red blood cells.
Metabolism

Busulfan is extensively metabolizes in the hepatic. Busulfan is predominantly metabolized by conjugation with glutathione, both spontaneously and by glutathione S-transferase (GST) catalysis. GSTA1 is the primary GST isoform that facilitates the the metabolism of busulfan. Other GST isoforms that are also involved are GSTM1 and GSTP1. At least 12 metabolites have been identified among which tetrahydrothiophene, tetrahydrothiophene 12-oxide, sulfolane, and 3-hydroxysulfolane were identified. These metabolites do not have cytotoxic activity.

Route of eliminationFollowing 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. Less than 2% of the administered dose is excreted in the urine unchanged within 24 hours. Elimination of busulfan is independent of renal function.
Half life2.6 hours
Clearance
  • 2.52 ml/min/kg [Following an infusion of dose of 0.8 mg/kg every six hours, for a total of 16 doses over four days]
ToxicitySigns 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.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9059
Blood Brain Barrier+0.9674
Caco-2 permeable-0.5956
P-glycoprotein substrateNon-substrate0.7556
P-glycoprotein inhibitor INon-inhibitor0.7224
P-glycoprotein inhibitor IINon-inhibitor0.9651
Renal organic cation transporterNon-inhibitor0.8617
CYP450 2C9 substrateNon-substrate0.8656
CYP450 2D6 substrateNon-substrate0.9115
CYP450 3A4 substrateNon-substrate0.5
CYP450 1A2 substrateNon-inhibitor0.8678
CYP450 2C9 inhibitorNon-inhibitor0.85
CYP450 2D6 inhibitorNon-inhibitor0.9159
CYP450 2C19 inhibitorNon-inhibitor0.7723
CYP450 3A4 inhibitorNon-inhibitor0.9855
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9069
Ames testAMES toxic0.9305
CarcinogenicityCarcinogens 0.7585
BiodegradationReady biodegradable0.5
Rat acute toxicity2.3207 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.6005
hERG inhibition (predictor II)Non-inhibitor0.8734
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
Manufacturers
  • Otsuka pharmaceutical co ltd
  • Glaxosmithkline
Packagers
Dosage forms
FormRouteStrength
Injectionintravenous6 mg/mL
Solutionintravenous6 mg
Tabletoral2 mg
Tablet, film coatedoral2 mg/1
Prices
Unit descriptionCostUnit
Busulfex 6 mg/ml vial115.08USD ml
Myleran 2 mg tablet4.55USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US5430057 No1994-03-302014-03-30Us
Properties
StateSolid
Experimental Properties
PropertyValueSource
melting point106-107Timmis, G.M.; U S . Patent 2,917,432; December 15, 1959; assigned to Burroughs Wellcome & Co., Inc.
water solubility6.9E+004 mg/LNot Available
logP-0.52HANSCH,C ET AL. (1995)
Predicted Properties
PropertyValueSource
Water Solubility5.16 mg/mLALOGPS
logP-0.9ALOGPS
logP-0.76ChemAxon
logS-1.7ALOGPS
Physiological Charge0ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area86.74 Å2ChemAxon
Rotatable Bond Count7ChemAxon
Refractivity49.57 m3·mol-1ChemAxon
Polarizability23.64 Å3ChemAxon
Number of Rings0ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
Spectra
Spectrum TypeDescriptionSplash Key
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, PositiveNot Available
1D NMR1H NMR SpectrumNot Available
1D NMR13C NMR SpectrumNot Available
References
Synthesis Reference

Timmis, G.M.; U S . Patent 2,917,432; December 15, 1959; assigned to Burroughs Wellcome
& Co., Inc.

US2917432
General References
  1. Lesurtel M, Graf R, Aleil B, Walther DJ, Tian Y, Jochum W, Gachet C, Bader M, Clavien PA: Platelet-derived serotonin mediates liver regeneration. Science. 2006 Apr 7;312(5770):104-7. [PubMed:16601191 ]
  2. Valdez BC, Andersson BS: Interstrand crosslink inducing agents in pretransplant conditioning therapy for hematologic malignancies. Environ Mol Mutagen. 2010 Jul;51(6):659-68. doi: 10.1002/em.20603. [PubMed:20577993 ]
  3. Hall AG, Tilby MJ: Mechanisms of action of, and modes of resistance to, alkylating agents used in the treatment of haematological malignancies. Blood Rev. 1992 Sep;6(3):163-73. [PubMed:1422285 ]
  4. Ciurea SO, Andersson BS: Busulfan in hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2009 May;15(5):523-36. doi: 10.1016/j.bbmt.2008.12.489. Epub 2009 Feb 12. [PubMed:19361744 ]
  5. McCune JS, Holmberg LA: Busulfan in hematopoietic stem cell transplant setting. Expert Opin Drug Metab Toxicol. 2009 Aug;5(8):957-69. doi: 10.1517/17425250903107764. [PubMed:19611402 ]
  6. Krivoy N, Hoffer E, Lurie Y, Bentur Y, Rowe JM: Busulfan use in hematopoietic stem cell transplantation: pharmacology, dose adjustment, safety and efficacy in adults and children. Curr Drug Saf. 2008 Jan;3(1):60-6. [PubMed:18690982 ]
  7. Nath CE, Shaw PJ: Busulphan in blood and marrow transplantation: dose, route, frequency and role of therapeutic drug monitoring. Curr Clin Pharmacol. 2007 Jan;2(1):75-91. [PubMed:18690856 ]
External Links
ATC CodesL01AB01
AHFS Codes
  • 10:00.00
PDB EntriesNot Available
FDA labelDownload (50.7 KB)
MSDSDownload (67.5 KB)
Interactions
Drug Interactions
Drug
AcetaminophenThe serum concentration of Busulfan can be increased when it is combined with Acetaminophen.
ClozapineThe risk or severity of adverse effects can be increased when Busulfan is combined with Clozapine.
DenosumabThe risk or severity of adverse effects can be increased when Denosumab is combined with Busulfan.
FluconazoleThe serum concentration of Busulfan can be increased when it is combined with Fluconazole.
FosphenytoinThe serum concentration of Busulfan can be decreased when it is combined with Fosphenytoin.
IfosfamideThe risk or severity of adverse effects can be increased when Busulfan is combined with Ifosfamide.
ItraconazoleThe serum concentration of Busulfan can be increased when it is combined with Itraconazole.
KetoconazoleThe serum concentration of Busulfan can be increased when it is combined with Ketoconazole.
LeflunomideThe risk or severity of adverse effects can be increased when Busulfan is combined with Leflunomide.
MetamizoleThe risk or severity of adverse effects can be increased when Metamizole is combined with Busulfan.
MetronidazoleThe serum concentration of Busulfan can be increased when it is combined with Metronidazole.
NatalizumabThe risk or severity of adverse effects can be increased when Busulfan is combined with Natalizumab.
PhenytoinThe serum concentration of Busulfan can be decreased when it is combined with Phenytoin.
PimecrolimusThe risk or severity of adverse effects can be increased when Pimecrolimus is combined with Busulfan.
PosaconazoleThe serum concentration of Busulfan can be increased when it is combined with Posaconazole.
PropacetamolThe serum concentration of Busulfan can be increased when it is combined with Propacetamol.
RoflumilastRoflumilast may increase the immunosuppressive activities of Busulfan.
Sipuleucel-TThe therapeutic efficacy of Sipuleucel-T can be decreased when used in combination with Busulfan.
TacrolimusThe risk or severity of adverse effects can be increased when Tacrolimus is combined with Busulfan.
TofacitinibBusulfan may increase the immunosuppressive activities of Tofacitinib.
TrastuzumabTrastuzumab may increase the neutropenic activities of Busulfan.
VoriconazoleThe serum concentration of Busulfan can be increased when it is combined with Voriconazole.
Food Interactions
  • Drink liberally.
  • Take without regard to meals.

Targets

1. DNA
Kind
Nucleotide
Organism
Human
Pharmacological action
yes
Actions
cross-linking/alkylation
General Function:
Used for biological information storage.
Specific Function:
DNA contains the instructions needed for an organism to develop, survive and reproduce.
Molecular Weight:
2.15 x 1012 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284 ]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed:17016423 ]
  3. Morales-Ramirez P, Gonzalez-Beltran F: Different behavior of SCE-eliciting lesions induced by low and high doses of busulfan. Environ Mol Mutagen. 2007 Oct;48(8):706-14. [PubMed:17896789 ]
  4. Valdez BC, Andersson BS: Interstrand crosslink inducing agents in pretransplant conditioning therapy for hematologic malignancies. Environ Mol Mutagen. 2010 Jul;51(6):659-68. doi: 10.1002/em.20603. [PubMed:20577993 ]
  5. Hall AG, Tilby MJ: Mechanisms of action of, and modes of resistance to, alkylating agents used in the treatment of haematological malignancies. Blood Rev. 1992 Sep;6(3):163-73. [PubMed:1422285 ]
  6. Ciurea SO, Andersson BS: Busulfan in hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2009 May;15(5):523-36. doi: 10.1016/j.bbmt.2008.12.489. Epub 2009 Feb 12. [PubMed:19361744 ]
  7. McCune JS, Holmberg LA: Busulfan in hematopoietic stem cell transplant setting. Expert Opin Drug Metab Toxicol. 2009 Aug;5(8):957-69. doi: 10.1517/17425250903107764. [PubMed:19611402 ]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Vitamin d3 25-hydroxylase activity
Specific Function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiot...
Gene Name:
CYP3A4
Uniprot ID:
P08684
Molecular Weight:
57342.67 Da
References
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Glutathione transferase activity
Specific Function:
Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles.
Gene Name:
GSTA2
Uniprot ID:
P09210
Molecular Weight:
25663.675 Da
References
  1. Vassord C, Lapoumeroulie C, Koumaravelou K, Srivastava A, Krishnamoorthy R: Endothelial cells do not express GSTA1: potential relevance to busulfan-mediated endothelial damage during haematopoietic stem cell transplantation. Eur J Haematol. 2008 Apr;80(4):299-302. doi: 10.1111/j.1600-0609.2008.01031.x. Epub 2008 Jan 14. [PubMed:18194479 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Glutathione transferase activity
Specific Function:
Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles.
Gene Name:
GSTA1
Uniprot ID:
P08263
Molecular Weight:
25630.785 Da
References
  1. Kusama M, Kubota T, Matsukura Y, Matsuno K, Ogawa S, Kanda Y, Iga T: Influence of glutathione S-transferase A1 polymorphism on the pharmacokinetics of busulfan. Clin Chim Acta. 2006 Jun;368(1-2):93-8. Epub 2006 Jan 31. [PubMed:16448639 ]
  2. Elhasid R, Krivoy N, Rowe JM, Sprecher E, Adler L, Elkin H, Efrati E: Influence of glutathione S-transferase A1, P1, M1, T1 polymorphisms on oral busulfan pharmacokinetics in children with congenital hemoglobinopathies undergoing hematopoietic stem cell transplantation. Pediatr Blood Cancer. 2010 Dec 1;55(6):1172-9. doi: 10.1002/pbc.22739. [PubMed:20672371 ]
  3. Vassord C, Lapoumeroulie C, Koumaravelou K, Srivastava A, Krishnamoorthy R: Endothelial cells do not express GSTA1: potential relevance to busulfan-mediated endothelial damage during haematopoietic stem cell transplantation. Eur J Haematol. 2008 Apr;80(4):299-302. doi: 10.1111/j.1600-0609.2008.01031.x. Epub 2008 Jan 14. [PubMed:18194479 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Protein homodimerization activity
Specific Function:
Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles.
Gene Name:
GSTM1
Uniprot ID:
P09488
Molecular Weight:
25711.555 Da
References
  1. Czerwinski M, Gibbs JP, Slattery JT: Busulfan conjugation by glutathione S-transferases alpha, mu, and pi. Drug Metab Dispos. 1996 Sep;24(9):1015-9. [PubMed:8886613 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
S-nitrosoglutathione binding
Specific Function:
Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles. Regulates negatively CDK5 activity via p25/p35 translocation to prevent neurodegeneration.
Gene Name:
GSTP1
Uniprot ID:
P09211
Molecular Weight:
23355.625 Da
References
  1. Czerwinski M, Gibbs JP, Slattery JT: Busulfan conjugation by glutathione S-transferases alpha, mu, and pi. Drug Metab Dispos. 1996 Sep;24(9):1015-9. [PubMed:8886613 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Leukotriene-c4 synthase activity
Specific Function:
Can catalyze the production of LTC4 from LTA4 and reduced glutathione. Can catalyze the conjugation of 1-chloro-2,4-dinitrobenzene with reduced glutathione.
Gene Name:
MGST2
Uniprot ID:
Q99735
Molecular Weight:
16620.4 Da
References
  1. Harkey MA, Czerwinski M, Slattery J, Kiem HP: Overexpression of glutathione-S-transferase, MGSTII, confers resistance to busulfan and melphalan. Cancer Invest. 2005;23(1):19-25. [PubMed:15779864 ]
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Drug created on June 13, 2005 07:24 / Updated on April 02, 2014 10:23