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| Trade names | Myleran, Busilvex, Busulfex IV |
| Other names | 1,4-butanediol dimethanesulfonate |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a682248 |
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| Routes of administration | By mouth,intravenous |
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| Pharmacokinetic data | |
| Bioavailability | 60–80% (oral) |
| Protein binding | 32.4% |
| Metabolism | Liver |
| Eliminationhalf-life | 2.5 hours |
| Excretion | Urine (25–60%) |
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| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.000.228 |
| Chemical and physical data | |
| Formula | C6H14O6S2 |
| Molar mass | 246.29 g·mol−1 |
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Busulfan (Myleran,GlaxoSmithKline,Busulfex IV,Otsuka America Pharmaceutical, Inc.) is achemotherapy drug in use since 1959. It is a cell cycle non-specificalkylating antineoplastic agent, in the class ofalkyl sulfonates. Its chemical designation is 1,4-butanediol dimethanesulfonate.
Busulfan was approved by the USFood and Drug Administration (FDA) for treatment ofchronic myeloid leukemia (CML) in 1999. Busulfan was the mainstay of thechemotherapeutic treatment ofchronic myeloid leukemia (CML) until it was displaced by the newgold standard,imatinib, though it is still in use to a degree as a result of the drug's relative low cost.
Busulfan is used in pediatrics and adults in combination withcyclophosphamide orfludarabine/clofarabine as a conditioning agent prior tobone marrow transplantation, especially inchronic myelogenous leukemia (CML) and otherleukemias,lymphomas, andmyeloproliferative disorders. Busulfan can control tumor burden but cannot prevent transformation or correct cytogenic abnormalities.
The drug was recently used in a study to examine the role of platelet-transportedserotonin inliver regeneration.[2]
Myleran is supplied in whitefilm coated tablets with 2 mg of busulfan per tablet. After 2002, a great interest has appeared for intravenous presentations of busulfan. Busulfex is supplied as an intravenous solution with 6 mg/ml busulfan. Busulfex has proved equally effective as oral busulfan, with presumedly less toxic side effects. Pharmacokinetic and dynamic studies support this use, that has prompted its usage in transplantation regimes, particularly in frail patients. Fludarabine + busulfan is a typical example of this use.
Toxicity may include interstitialpulmonary fibrosis ("busulfan lung"),hyperpigmentation,seizures, hepatic (veno-occlusive disease) (VOD) or sinusoidal obstruction syndrome (SOS),[3][4]emesis, andwasting syndrome. Busulfan also induces impotence in males (kills germ cells),thrombocytopenia, a condition of lowered bloodplatelet count and activity, and sometimes medullaryaplasia.[5] Seizures and VOD are serious concerns with busulfan therapy and prophylaxis is often utilized to avoid these effects. Hepatic VOD is a dose-limiting toxicity. Symptoms of VOD include weight gain, elevatedbilirubin, painfulhepatomegaly, andedema. The reason busulfan causes VOD is mostly unknown and can be deadly.[4]Ursodiol may be considered for prophylaxis of veno-occlusive disease.
Antiemetics are often administered prior to busulfan to prevent vomiting (emesis).
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.[6]
Busulfan is listed by theIARC as a Group 1carcinogen.
As an adjunct therapy withcyclophosphamide for conditioning prior tobone marrow transplantation in adults and children >12 kg, intravenous (IV) busulfan (Bulsulfex) is dosed at 0.8 mg/kg every six hours for 16 doses (four days). IV busulfan is usually administered over two hours. Both IV and oral formulations require prophylacticantiemetic agents administered prior to the busulfan dose and scheduledantiemetics administered thereafter. Oral bioavailability of busulfan shows a large interindividual variation.[7] Taking busulfan on an empty stomach is recommended to reduce the risk ofnausea andemesis.
Peak plasma concentrations are achieved within one hour of oral administration. About 30% of the drug is bound to plasma proteins, such asalbumin.
Busulfantherapeutic drug monitoring is completed based on trough (pre-dose) levels with a target six-hourarea under the curve (AUC) of between 900 and 1500 micromolxmin. AUCs (six-hour) >1500 micromolxmin are associated with hepatic VOD and subsequent dose reduction should be considered. AUCs (six-hour) <900 micromolxmin are associated with incompletebone marrowablation and subsequent dose escalation should be considered. Dose adjustments are performed usingfirst order kinetics, such that the adjusted dose = current dose × (target AUC/actual AUC).
Busulfan is metabolized viaglutathione conjugation in the liver to inactivemetabolites.Itraconazole can decrease busulfan clearance by up to 25%, resulting in AUC levels >1500 micromolxmin and increased risk of hepatic VOD. Concomitant use ofacetaminophen within 72 hours of busulfan use can reduce busulfan clearance (resulting in increased busulfan AUC), asacetaminophen is also metabolized viaglutathione and may deplete stores.Phenytoin increases hepatic clearance of busulfan (resulting in decreased busulfan AUC). However, clinical studies of busulfan were completed with patients taking phenytoin, so no empiric dose adjustment is necessary if patients are takingphenytoin with busulfan.
Busulfan is analkylsulfonate. It is analkylating agent that forms DNA-DNAinterstrand crosslinks between theDNA basesguanine andadenine and betweenguanine andguanine.[8] This occurs through anSN2 reaction in which the relativelynucleophilic guanine N7 attacks the carbon adjacent to themesylate leaving group.DNA crosslinking preventsDNA replication. Because the intrastrand DNA crosslinks cannot be repaired by cellular machinery, the cell undergoesapoptosis.[9]
The molecular recognition of ureido-cyclodextrin with busulfan was investigated.[10] The formation of complexes was observed with electrostatic interactions between urea and thesulfonate part of busulfan.
Another structure was used for this complexation type, two disaccharidyl units connected by urea linkers to a diazacrown ether organizing platform.[11]
