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Identification
Name Busulfan
Accession Number DB01008 (APRD00664)
Type small molecule
Groups approved
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. [PubChem]
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • busulfan
  • Busulphan
  • Busulphane
  • Butanedioldimethanesulfonate
  • Buzulfan
  • Sulfabutin
  • Sulphabutin
  • Tetramethylene Dimethane Sulfonate
  • Tetramethylenester Kyseliny Methansulfonove
Brand names
  • Busulfex
  • Citosulfan
  • Leucosulfan
  • Mablin
  • Mielevcin
  • Mielosan
  • Mielucin
  • Milecitan
  • Mileran
  • Misulban
  • Mitosan
  • Mitostan
  • Myeleukon
  • Myeloleukon
  • Myelosan
  • Mylecytan
  • Myleran
  • Myleran Tablets
Brand name mixtures Not Available
Categories
  • Antineoplastic Agents
  • Immunosuppressive Agents
  • Alkylating Agents
  • Antineoplastic Agents, Alkylating
  • Myeloablative Agonists
CAS number 55-98-1
Weight Average: 246.302
Monoisotopic: 246.023179560
Chemical Formula C6H14O6S2
InChI Key InChIKey=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
Plain Text
IUPAC Name
4-(methanesulfonyloxy)butyl methanesulfonate
SMILES
CS(=O)(=O)OCCCCOS(C)(=O)=O
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Sulfonyls
Substructures
  • Sulfonyls
Pharmacology
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.
Pharmacodynamics 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.
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.
Absorption Completely absorbed from the gastrointestinal tract.
Volume of distribution Not Available
Protein binding 32.4%
Metabolism

Mainly Hepatic. Busulfan is predominantly metabolized by conjugation with glutathione, both spontaneously and by glutathione S-transferase (GST) catalysis.
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.
Half life 2.5 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]
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.
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Otsuka pharmaceutical co ltd
  • Glaxosmithkline
Packagers
Dosage forms
Form Route Strength
Solution Intravenous
Tablet Oral
Prices
Unit description Cost Unit
Busulfex 6 mg/ml vial 115.08 USD ml
Myleran 2 mg tablet 4.55 USD tablet
Patents
Country Patent Number Approved Expires
United States 5430057 1994-03-30 2014-03-30
Properties
State solid
Melting point 287 oC
Experimental Properties
Property Value Source
water solubility 6.9E+004 mg/L PhysProp
logP -0.3 PhysProp
Predicted Properties
Property Value Source
water solubility 5.16e+00 g/l ALOGPS
logP -0.90 ALOGPS
logP -0.76 ChemAxon Molconvert
logS -1.68 ALOGPS
pKa ChemAxon Molconvert
hydrogen acceptor count 4 ChemAxon Molconvert
hydrogen donor count 0 ChemAxon Molconvert
polar surface area 86.74 ChemAxon Molconvert
rotatable bond count 7 ChemAxon Molconvert
refractivity 49.57 ChemAxon Molconvert
polarizability 23.64 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference
  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
  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. Pubmed
  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
  4. Ciurea SO, Andersson BS: Busulfan in hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2009 May;15(5):523-36. Epub 2009 Feb 12. Pubmed
  5. McCune JS, Holmberg LA: Busulfan in hematopoietic stem cell transplant setting. Expert Opin Drug Metab Toxicol. 2009 Aug;5(8):957-69. Pubmed
  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
  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
External Links
Resource Link
KEGG Drug D00248 Link_out
PubChem Compound 2478 Link_out
PubChem Substance 46506234 Link_out
ChemSpider 2384 Link_out
ChEBI 28901 Link_out
ChEMBL 28901 Link_out
PharmGKB PA448691 Link_out
Drug Product Database 2240602 Link_out
RxList http://www.rxlist.com/cgi/generic2/busulfan.htm Link_out
Drugs.com http://www.drugs.com/cdi/busulfan.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Busulfan Link_out
ATC Codes
  • L01AB01
AHFS Codes
  • 10:00.00
PDB Entries Not Available
FDA label show (50.7 KB)
MSDS show (67.5 KB)
Interactions
Drug Interactions Not Available
Food Interactions
  • Drink liberally.
  • Take without regard to meals.
Targets

1. DNA

Pharmacological action: yes
Actions: cross-linking/alkylation

DNA is the molecule of heredity, as it is responsible for the genetic propagation of most inherited traits. It is a polynucleic acid that carries genetic information on cell growth, division, and function. DNA consists of two long strands of nucleotides twisted into a double helix and held together by hydrogen bonds. The sequence of nucleotides determines hereditary characteristics. Each strand serves as the template for subsequent DNA replication and as a template for mRNA production, leading to protein synthesis via ribosomes.

Gene Sequence: FASTA

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
  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
  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 Sep 26;48(8):706-714. Pubmed
  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. Pubmed
  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
  6. Ciurea SO, Andersson BS: Busulfan in hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2009 May;15(5):523-36. Epub 2009 Feb 12. Pubmed
  7. McCune JS, Holmberg LA: Busulfan in hematopoietic stem cell transplant setting. Expert Opin Drug Metab Toxicol. 2009 Aug;5(8):957-69. Pubmed
Enzymes

1. Cytochrome P450 3A4

Actions: substrate

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 xenobiotics. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out
Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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. Epub 2009 Nov 24. Pubmed

2. Glutathione S-transferase A2

Actions: substrate

Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles

UniProt ID: P09210 Link_out
Gene: GSTA2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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. Epub 2008 Jan 14. Pubmed

3. Glutathione S-transferase A1

Actions: substrate

Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles

UniProt ID: P08263 Link_out
Gene: GSTA1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
  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. Pubmed
  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. Epub 2008 Jan 14. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on August 18, 2011 10:57

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.