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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/11/10 11:32:35」(JST)

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Busulfan (Myleran, GlaxoSmithKline, Busulfex IV, Otsuka America Pharmaceutical, 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.

History

Busulfan was approved by the US Food and Drug Administration (FDA) for treatment of chronic myeloid leukemia (CML) in 1999. 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

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.

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. 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.

Side effects

Toxicity may include interstitial pulmonary fibrosis ("Busulfan Lung"), hyperpigmentation, seizures, hepatic (veno-occlusive disease) (VOD), emesis, and wasting syndrome. Busulfan also induces thrombocytopenia, a condition of lowered blood platelet count and activity. 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.

Antiemetics are often administered prior to busulfan to prevent 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.^[2]

Ursodiol may be considered for prophylaxis of veno-occlusive disease.

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

Dosing, Administration, and Pharmacokinetics

As an adjunct therapy with cyclophosphamide for conditioning prior to bone marrow transplantation in adults and children >12 kg, intravenous (IV) busulfan (Bulsulfex) is dosed at 0.8 mg/kg every 6 hours for 16 doses (4 days). IV busulfan is usually administered over two hours. Both IV and oral formulations require prophylactic antiemetic agents administered prior to the busulfan dose and scheduled antiemetics administered thereafter. Taking busulfan on an empty stomach is recommended to reduce the risk of nausea and emesis.

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 therapeutic drug monitoring is completed based on trough (pre-dose) levels with a target 6-hour area under the curve (AUC) of between 900 and 1500 micromolxmin. AUCs (6-hour) >1500 micromolxmin are associated with hepatic VOD and subsequent dose reduction should be considered. AUCs (6-hour) <900 micromolxmin are associated with incomplete bone marrow ablation and subsequent dose escalation should be considered. Dose adjustments are performed using first order kinetics, such that the adjusted dose = current dose x (target AUC/actual AUC).

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

Busulfan is an alkylsulfonate. It's an alkylating agent that forms DNA-DNA intrastrand crosslinks between the DNA bases guanine and adenine and between guanine and guanine.^[3] 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.^[4]

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.

Another structure was used for this complexation type, two disaccharidyl units connected by urea linkers to a diazacrown ether organizing platform.^[6]

Synthesis

Busulfan synthesis: GB 700677 U.S. Patent 2,917,432.

Ms = mesyl (MeSO₂)

References

^ Lesurtel M, Graf R, Aleil B, Walther D, Tian Y, Jochum W, Gachet C, Bader M, Clavien P (2006). "Platelet-derived serotonin mediates liver regeneration". Science 312 (5770): 104–7. doi:10.1126/science.1123842. PMID 16601191.
^ Eberly, AL.; Anderson, GD.; Bubalo, JS.; McCune, JS. (Dec 2008). "Optimal prevention of seizures induced by high-dose busulfan.". Pharmacotherapy 28 (12): 1502–10. doi:10.1592/phco.28.12.1502. PMID 19025431.
^ Iwamoto T, Hiraku Y, Oikawa S, Mizutani H, Kojima M, Kawanishi S (May 2004). "DNA intrastrand cross-link at the 5'-GA-3' sequence formed by busulfan and its role in the cytotoxic effect". Cancer Sci. 95 (5): 454–8. doi:10.1111/j.1349-7006.2004.tb03231.x. PMID 15132775.
^ Karstens A, Kramer I (2007). "Chemical and physical stability of diluted busulfan infusion solutions". EJHP Science 13: 40–7.
^ Menuel S, Joly JP, Courcot B, Elysee J, Ghermani NE, Marsura A (2007). "Synthesis and inclusion ability of a bis-beta-cyclodextrin pseudo-cryptand towards Busulfan anticancer agent". Tetrahedron 63 (7): 1706–14. doi:10.1016/j.tet.2006.10.070.
^ Porwanski S, Florence DCB, Menuel S, Joly JP, Bulach V, Marsura A (2009). "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. doi:10.1016/j.tet.2009.05.057.

External links

Myleran (PDF prescribing information)
Busulfex (PDF prescribing information)
Detailed information
Pub Med Health
Cancer Help UK

UpToDate Contents

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1. ブスルファン誘発性肺損傷 busulfan induced pulmonary injury
2. 非プラチナ製剤ベースの癌化学療法の神経学的合併症の概要 overview of neurologic complications of non platinum cancer chemotherapy
3. 造血細胞移植のための前処置療法 preparative regimens for hematopoietic cell transplantation
4. 造血細胞移植後の肝類洞閉塞症候群（静脈閉塞性疾患）の診断 diagnosis of hepatic sinusoidal obstruction syndrome veno occlusive disease following hematopoietic cell transplantation
5. 真性多血症の予後および治療 prognosis and treatment of polycythemia vera

English Journal

Allogeneic Hematopoietic Stem Cell Transplantation in Thirty-Four Pediatric Cases of Mucopolysaccharidosis-A Ten-Year Report from the China Children Transplant Group.

Wang J1, Luan Z2, Jiang H3, Fang J4, Qin M5, Lee V6, Chen J7.
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.Biol Blood Marrow Transplant.2016 Nov;22(11):2104-2108. doi: 10.1016/j.bbmt.2016.08.015. Epub 2016 Aug 20.
We investigated the efficacy of allogeneic hematopoietic stem cell transplantation (alloHSCT) in pediatric patients with mucopolysaccharidosis (MPS). A retrospective analysis of transplantation data from 34 cases of MPS from the China Children Transplant Group, treated between December 2004 and Sept
PMID 27555533

A Single-Center Experience Comparing Alemtuzumab, Fludarabine, and Melphalan Reduced-Intensity Conditioning with Myeloablative Busulfan, Cyclophosphamide, and Antithymocyte Globulin for Chronic Granulomatous Disease.

Khandelwal P1, Bleesing JJ2, Davies SM2, Marsh RA2.
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.Biol Blood Marrow Transplant.2016 Nov;22(11):2011-2018. doi: 10.1016/j.bbmt.2016.08.013. Epub 2016 Aug 16.
Myeloablative conditioning (MAC) regimens are commonly used in transplantation for chronic granulomatous disease (CGD) but are associated with toxicity. Reduced-intensity conditioning (RIC) regimens have lower toxicity but may fail to achieve stable donor chimerism. We report a comparison between 4
PMID 27543157

Personalizing Busulfan-Based Conditioning: Considerations from the American Society for Blood and Marrow Transplantation Practice Guidelines Committee.

Palmer J1, McCune JS2, Perales MA3, Marks D4, Bubalo J5, Mohty M6, Wingard JR7, Paci A8, Hassan M9, Bredeson C10, Pidala J11, Shah N12, Shaughnessy P13, Majhail N14, Schriber J15, Savani BN16, Carpenter PA17.
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.Biol Blood Marrow Transplant.2016 Nov;22(11):1915-1925. doi: 10.1016/j.bbmt.2016.07.013. Epub 2016 Jul 29.
The Practice Guidelines Committee of the American Society of Blood or Marrow Transplantation (ASBMT) sought to develop an evidence-based review about personalizing busulfan-based conditioning. The Committee sought to grade the relevant published studies (June 1, 2008 through March 31, 2016) accordin
PMID 27481448

Japanese Journal

ラット橈側列欠損モデルにおける肢芽細胞死と皮膚紋理の解析

小瀧宏明,加藤博之,三浪明男,津金瑞代,濃野勉
日本手の外科学会雑誌 = The Journal of Japanese Society for Surgery of the Hand 15(6), 799-802, 1999-02-28
NAID 10010060267

ラット橈側列欠損の発生メカニズム : 肢芽細胞死と皮膚紋理の解析

小瀧宏明,三浪明男,加藤博之,金田清志,津金瑞代,濃野勉
日本整形外科學會雜誌 = The Journal of the Japanese Orthopaedic Association 72(8), S1562, 1998-08-25
NAID 10016496273

Clinical and Experimental Studies on Teratogenic Mechanisms of Congenital Absence of Digits in Longitudinal Deficiencies

荻野利彦,加藤博之
先天異常 33(3), 187-196, 1993-09-30
NAID 110002787193

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★リンクテーブル★

リンク元	「ブスルファン」
関連記事	「myleran」

「ブスルファン」

Busulfan
Systematic (IUPAC) name
	butane-1,4-diyl dimethanesulfonate
Clinical data
Trade names	Myleran
AHFS/Drugs.com	monograph
MedlinePlus	a682248
Licence data	US FDA:link
Pregnancy cat.	AU: D; US: D;
Legal status	AU: Prescription Only (S4); CA: ℞-only; UK: POM; US: ℞-only;
Routes	Oral, IV
Pharmacokinetic data
Bioavailability	60-80% (oral)
Protein binding	32.4%
Metabolism	Hepatic
Half-life	2.5 hours
Excretion	Urine (25-60%)
Identifiers
CAS number	55-98-1
ATC code	L01AB01
PubChem	CID 2478
DrugBank	DB01008
ChemSpider	2384
UNII	G1LN9045DK
KEGG	D00248
ChEBI	CHEBI:28901
ChEMBL	CHEMBL820
Synonyms	1,4-butanediol dimethanesulfonate
Chemical data
Formula	C6H14O6S2
Mol. mass	246.304 g/mol
	SMILES O=S(=O)(OCCCCOS(=O)(=O)C)C;
	InChI InChI=1S/C6H14O6S2/c1-13(7,8)11-5-3-4-6-12-14(2,9)10/h3-6H2,1-2H3 ; Key:COVZYZSDYWQREU-UHFFFAOYSA-N ;
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