Busulfan

Busulfan
Systematic (IUPAC) name
butane-1,4-diyl dimethanesulfonate
Identifiers
CAS number 55-98-1
ATC code L01AB01
PubChem CID 2478
DrugBank APRD00664
ChemSpider 2384
UNII G1LN9045DK
ChEMBL CHEMBL820
Chemical data
Formula C6H14O6S2 
Mol. mass 246.304 g/mol
SMILES eMolecules & PubChem
Synonyms 1,4-butanediol dimethanesulfonate
Pharmacokinetic data
Bioavailability 80% (oral)
Protein binding 32.4%
Metabolism Hepatic
Half-life 2.5 hours
Excretion ?
Therapeutic considerations
Licence data EMA:[ Link]US FDA:link
Pregnancy cat. D(US)
Legal status Prescription only
Routes Oral, parenteral
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Busulfan (Myleran, GlaxoSmithKline, Busulfex IV, PDL BioPharma, Inc.) is a cancer drug, in use since 1959.

Busulfan is a cell cycle non-specific alkylating antineoplastic agent, in the class of alkyl sulfonates. Its chemical designation is 1,4-butanediol dimethanesulfonate.

Contents


History

Busulfan was the mainstay of the chemotherapeutic treatment of chronic myeloid leukemia (CML) until it was displaced by the new gold standard, imatinib, though it is still in use to a degree as a result of the drug's relative low cost.

Indications

Currently, its main uses are in bone marrow transplantation, especially in chronic myelogenous leukemia (CML), where it is used as a conditioning drug. Busulfan can control tumor burden but cannot prevent transformation or correct cytogenic abnormalities. Though not as common, it may also be used for chronic lymphocytic leukemia (CLL). The drug was recently used in a study to examine the role of platelet-transported serotonin in liver regeneration.[1]

Availability

Myleran is supplied in white film coated tablets with 2 mg of busulfan per tablet.

Side effects

Toxicity may include interstitial pulmonary fibrosis, hyperpigmentation, seizures, hepatic (veno-occlusive disease) and wasting syndrome. Phenytoin may be used concurrently to prevent the seizures. Levetiracetam, has shown efficacy for the prophylaxis against busulfan-induced seizures. Benzodiazepines can also be used for busulfan-induced seizures.[2]

Busulfan is listed by the IARC as a Group 1 carcinogen.

Pharmacology

Its mechanism of action through alkylation produces guanine-adenine intrastrand crosslinks.[3] 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.[4] Busulfan also induces thrombocytopenia, a condition of lowered blood platelet count and activity.

Complexation

The molecular recognition of ureido-cyclodextrin with busulfan was investigated.[5] The formation of complexes was observed with electrostatic interactions between urea and the sulfonate part of busulfan. A other structure was used for this complextation type, two disaccharidyl units connected by urea linkers to a diazacrown ether organizing platform.[6]

References

  1. Lesurtel M, Graf R, Aleil B, Walther D, Tian Y, Jochum W, Gachet C, Bader M, Clavien P (2006). . Science 312 (5770): 104–7. . . 
  2. Eberly, AL.; Anderson, GD.; Bubalo, JS.; McCune, JS. (Dec 2008). . Pharmacotherapy 28 (12): 1502–10. . . 
  3. Iwamoto, T; et al. "DNA intrastrand cross-link at the 5'-GA-3' sequence formed by busulfan and its role in the cytotoxic effect" Cancer Science 2004 95 pp 454-458
  4. Karstens, A; Kramer, I. "Chemical and physical stability of diluted busulfan infusion solutions". EJHP Science 2007 13 pp 40-47
  5. Menuel S, Joly JP, Courcot B, Elysee J, Ghermani NE, Marsura A (2007). . Tetrahedron 63 (7): 1706–1714. . 
  6. Porwanski S, Florence DCB, Menuel S, Joly JP, Bulach V, Marsura A (2009). . Tetrahedron 65 (31): 6196–6203. .