Chemistry:Busulfan

From HandWiki

Busulfan (Myleran, GlaxoSmithKline; Busulfex IV, Otsuka America Pharmaceutical, Inc.) is a chemotherapy drug that has been in use since 1959. It is a cell cycle-nonspecific alkylating antineoplastic agent belonging to the alkyl sulfonates class. Its chemical designation is 1,4-butanediol dimethanesulfonate.

Medical uses

Busulfan is used in pediatrics and adults in combination with cyclophosphamide or fludarabine/clofarabine as a conditioning agent prior to bone marrow transplantation, especially in chronic myelogenous leukemia (CML) and other leukemias, lymphomas, and myeloproliferative disorders. Busulfan can control tumor burden but cannot prevent transformation or correct cytogenic abnormalities.

Busulfan was formerly used as a palliative treatment for chronic myeloid leukemia (CML). Its role in the routine treatment of CML declined following the introduction for tyrosine kinase inhibitors, beginning with imatinib in 2001.[1] Current CML treatment is based primarily on tyrosine kinase inhibitors, while busulfan remains in use mainly as part of conditioning regimens before hematopoietic stem-cell transplantation.

Available forms

The intravenous formulation, marketed as Busulfex, received approval from the United States Food and Drug Administration (FDA) in 1999 [2] for use with cyclophosphamide as a conditioning regimen before allogeneic hematopoietic progenitor cell transplantation in patients with chronic myeloid leukemia (CML). It had received orphan-drug designation for preparative therapy associated with bone-marrow transplantation in 1994.

Myleran is supplied in white film 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.

Busulfan is used as an adjunct therapy with cyclophosphamide or other chemotherapeutic agents for conditioning prior to bone marrow transplantation. In adults and children >34 kg, intravenous (IV) busulfan (Bulsulfex) is commonly dosed at 3.2 mg/kg/day administered every six hours (4 times daily) or 24 hours (once daily). Once daily dosing is commonly administered over 3 hours while four times daily is commonly administered over two hours.[3] Both IV and oral formulations require prophylactic antiemetic agents administered prior to the busulfan dose and scheduled antiemetics administered thereafter. Oral bioavailability of busulfan shows a large interindividual variation. Taking busulfan on an empty stomach is recommended to reduce the risk of nausea and emesis.

Side effects

Toxicity may include interstitial pulmonary fibrosis ("busulfan lung"), hyperpigmentation, seizures, hepatic veno-occlusive disease (VOD) or sinusoidal obstruction syndrome (SOS),[4][5] emesis, and wasting syndrome. Busulfan also induces impotence in males (kills germ cells), thrombocytopenia, a condition of lowered blood platelet count and activity, and sometimes medullary aplasia.[6] 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, elevated bilirubin, painful hepatomegaly, and edema. The reason busulfan causes VOD is mostly unknown and can be deadly. [5] 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 prophylaxis against busulfan-induced seizures. Benzodiazepines can also be used for busulfan-induced seizures.[7]

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

Drug interactions

Busulfan is metabolized via glutathione conjugation in the liver to inactive metabolites. Itraconazole can decrease busulfan clearance by up to 25%, resulting in AUC levels >1500 micromolxmin and increased risk of hepatic VOD. Concomitant use of acetaminophen within 72 hours of busulfan use can reduce busulfan clearance (resulting in increased busulfan AUC), as acetaminophen is also metabolized via glutathione 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 taking phenytoin with busulfan.

Pharmacology

Pharmacokinetics

Peak plasma concentrations are achieved within one hour of oral administration. About 30% of the drug is bound to plasma proteins, such as albumin.

Busulfan exhibits high interindividual pharmacokinetic variability, narrow therapeutic window, and a well-established correlation between pharmacokinetics and pharmacodynamics. In fact, the cumulative area under the curve over the treatment period (AUC0-4 days) is highly correlated with treatment outcomes. While subtherapeutic exposure increases the risk of graft failure and disease relapse, supratherapeutic exposures increases the risk of treatment related toxicity, mainly in the form of hepatic Veno occlusive disease (VOD). Therefore, therapeutic drug monitoring and model-informed precision dosing are widely recommended to individualize busulfan dosing.[8]

Busulfan exposure is assessed using the area under the plasma concentration–time curve (AUC), rather than a single trough concentration. AUC may be estimated from multiple concentration measurements using noncompartmental pharmacokinetic methods or population pharmacokinetic and Bayesian approaches with limited sampling strategies. The target cumulative busulfan exposure varies depending on the underlying disease and transplantation setting, with target cumulative AUC over the four days of treatment generally ranging from 78 to 100 mg*h/L.[9][10]

Pharmacodynamics

Busulfan is an alkylsulfonate. It is an alkylating agent that forms DNA-DNA interstrand crosslinks between the DNA bases guanine and adenine and between guanine and guanine.[11] This occurs through an SN2 reaction in which the relatively nucleophilic guanine N7 attacks the carbon adjacent to the mesylate leaving group. DNA crosslinking prevents DNA replication. Because the intrastrand DNA crosslinks cannot be repaired by cellular machinery, the cell undergoes apoptosis.[12]

Research

The drug was recently used in a study to examine the role of platelet-transported serotonin in liver regeneration.[13]

The molecular recognition of ureido-cyclodextrin with busulfan was investigated.[14] The formation of complexes was observed with electrostatic interactions between urea and the sulfonate part of busulfan.

Another structure was used for this complexation type, two disaccharidyl units connected by urea linkers to a diazacrown ether organizing platform.[15]

References

  1. ↑ "Busulfan". 2022-02-21. https://www.acs.org/molecule-of-the-week/archive/b/busulfan.html. 
  2. ↑ "FDA Approves Busulfex Injection | CancerNetwork". CancerNetwork. 2026-07-16. https://www.cancernetwork.com/view/fda-approves-busulfex-injection. 
  3. ↑ "Once-Daily Versus Four-Times-Daily Intravenous Busulfan with Therapeutic Drug Monitoring as Conditioning for Hematopoietic Cell Transplantation in Children". Pharmaceutics 17 (8): 1081. August 2025. doi:10.3390/pharmaceutics17081081. PMID 40871100. 
  4. ↑ "Acute portal vein thrombosis after autologous stem cell transplantation". Bone Marrow Transplantation 18 (5): 949–953. 1996. PMID 8932850. 
  5. ↑ 5.0 5.1 "Portal vein thrombosis during antineoplastic chemotherapy in children: report of five cases and review of the literature". European Journal of Cancer (Oxford) 40 (18): 2659–2666. 2004. doi:10.1016/j.ejca.2004.06.013. PMID 15571949. 
  6. ↑ "Medullary aplasia in chronic myeloid leukaemia during busulphan therapy". British Medical Journal 2 (5059): 1468–1471. 1957. doi:10.1136/bmj.2.5059.1468. PMID 13489262. 
  7. ↑ "Optimal prevention of seizures induced by high-dose busulfan". Pharmacotherapy 28 (12): 1502–1510. December 2008. doi:10.1592/phco.28.12.1502. PMID 19025431. 
  8. ↑ "Busulfan in infant to adult hematopoietic cell transplant recipients: a population pharmacokinetic model for initial and Bayesian dose personalization". Clinical Cancer Research 20 (3): 754–763. February 2014. doi:10.1158/1078-0432.CCR-13-1960. PMID 24218510. 
  9. ↑ "A practical guide to therapeutic drug monitoring in busulfan: recommendations from the Pharmacist Committee of the European Society for Blood and Marrow Transplantation (EBMT)". Bone Marrow Transplantation 59 (12): 1641–1653. December 2024. doi:10.1038/s41409-024-02413-0. PMID 39271948. 
  10. ↑ "Association of busulfan exposure with survival and toxicity after haemopoietic cell transplantation in children and young adults: a multicentre, retrospective cohort analysis". The Lancet. Haematology 3 (11): e526–e536. November 2016. doi:10.1016/S2352-3026(16)30114-4. PMID 27746112. 
  11. ↑ "DNA intrastrand cross-link at the 5'-GA-3' sequence formed by busulfan and its role in the cytotoxic effect". Cancer Science 95 (5): 454–458. May 2004. doi:10.1111/j.1349-7006.2004.tb03231.x. PMID 15132775. 
  12. ↑ "Chemical and physical stability of diluted busulfan infusion solutions". EJHP Science 13: 40–47. 2007. 
  13. ↑ "Platelet-derived serotonin mediates liver regeneration". Science (New York, N.Y.) 312 (5770): 104–107. 2006. doi:10.1126/science.1123842. PMID 16601191. Bibcode: 2006Sci...312..104L. 
  14. ↑ "Synthesis and inclusion ability of a bis-beta-cyclodextrin pseudo-cryptand towards Busulfan anticancer agent". Tetrahedron 63 (7): 1706–1714. 2007. doi:10.1016/j.tet.2006.10.070. 
  15. ↑ "Bis-beta-cyclodextrinyl- and bis-cellobiosyl-diazacrowns: synthesis and molecular complexation behaviors toward Busulfan anticancer agent and two basic aminoacids". Tetrahedron 65 (31): 6196–6203. 2009. doi:10.1016/j.tet.2009.05.057. 



Retrieved from "https://handwiki.org/wiki/index.php?title=Chemistry:Busulfan&oldid=4645576"