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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/06/21 03:06:56」(JST)

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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 category	AU: D US: D (Evidence of risk)
Legal status	AU: Prescription Only (S4) CA: ℞-only UK: Prescription-only (POM) US: ℞-only
Routes of administration	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 Registry Number	55-98-1 Y
ATC code	L01AB01
PubChem	CID: 2478
IUPHAR/BPS	7136
DrugBank	DB01008 Y
ChemSpider	2384 Y
UNII	G1LN9045DK Y
KEGG	D00248 Y
ChEBI	CHEBI:28901 Y
ChEMBL	CHEMBL820 Y
Synonyms	1,4-butanediol dimethanesulfonate
Chemical data
Formula	C6H14O6S2
Molecular 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  Y Key:COVZYZSDYWQREU-UHFFFAOYSA-N  Y
Y (what is this?)  (verify)

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.

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.

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. 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.

Complexation

The molecular recognition of ureido-cyclodextrin with busulfan was investigated. 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.

Synthesis

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

Ms = mesyl (MeSO₂)

References

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. アントラサイクリン系以外の癌化学療法剤の心毒性 cardiotoxicity of nonanthracycline cancer chemotherapy agents
• 4. 造血細胞移植のための前処置療法 preparative regimens for 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

• Fludarabine, cytarabine, granulocyte colony-stimulating factor and melphalan (FALG with L-PAM) as a reduced toxicity conditioning regimen in children with acute leukemia.

• Kato K, Yoshida N, Matsumoto K, Matsuyama T.Author information Department of Pediatric Hematology and Oncology, Children's Medical Center, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan.AbstractBACKGROUND: The conventional conditioning regimen for patients with leukemia prior to allogeneic stem cell transplantation is myeloablation to eradicate residual leukemic cells and host immunocompetent cells. This helps prevent leukemic relapse as well as rejection after transplantation. A myeloablative conditioning regimen with busulfan (BU) or total body irradiation (TBI) is effective for eradication of leukemic cells but is also associated with significant toxicities in the acute or late phase in pediatric patients. In an effort to minimize these adverse effects, we conducted bone marrow transplantation (BMT) from unrelated volunteer donors using a conditioning regimen without BU or TBI.
• Pediatric blood & cancer.Pediatr Blood Cancer.2014 Apr;61(4):712-6. doi: 10.1002/pbc.24922. Epub 2013 Dec 30.
• BACKGROUND: The conventional conditioning regimen for patients with leukemia prior to allogeneic stem cell transplantation is myeloablation to eradicate residual leukemic cells and host immunocompetent cells. This helps prevent leukemic relapse as well as rejection after transplantation. A myeloabla
• PMID 24376191

• Gas chromatographic-mass spectrometric quantitation of busulfan in human plasma for therapeutic drug monitoring: A new on-line derivatization procedure for the conversion of busulfan to 1,4-diiodobutane.

• Athanasiadou I1, Angelis YS2, Lyris E3, Archontaki H4, Georgakopoulos C5, Valsami G6.Author information 1Doping Control Laboratory of Athens, Olympic Athletic Center of Athens, Kifissias 37, 15123 Maroussi, Greece; Laboratory of Biopharmaceutics and Pharmacokinetics, School of Pharmacy, University of Athens, Panepistimiopolis-Zographou, 15771 Athens, Greece.2Doping Control Laboratory of Athens, Olympic Athletic Center of Athens, Kifissias 37, 15123 Maroussi, Greece. Electronic address: oaka@ath.forthnet.gr.3Doping Control Laboratory of Athens, Olympic Athletic Center of Athens, Kifissias 37, 15123 Maroussi, Greece.4Laboratory of Analytical Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis-Zographou, 15771 Athens, Greece.5Anti Doping Laboratory, P.O. Box 27775 Doha, Qatar.6Laboratory of Biopharmaceutics and Pharmacokinetics, School of Pharmacy, University of Athens, Panepistimiopolis-Zographou, 15771 Athens, Greece.AbstractA simplified gas chromatographic-mass spectrometric (GC-MS) analytical method, involving a novel derivatization procedure was developed for monitoring busulfan (Bu) plasma concentrations in populations undergoing bone marrow transplantation. Plasma samples (500μL) containing Bu-d8 as internal standard were extracted with ethyl acetate (2mL) followed by centrifugation (1800rpm, 5min) and evaporation of the organic layer under nitrogen flow (50°C). The dry residue was reconstituted with 100μL iodine solution in acetonitrile (0.25%, w/v) and 3μL were injected into the GC-MS system at 250°C. Conversion of Bu to 1,4-diiodobutane was accomplished on-line without the need of an extra derivatization step. MS was operated at selected ion monitoring mode at m/z 183 and 191 corresponding to Bu and Bu-d8 derivatives. Total analysis time was 11.5min. Calibration curves were linear (mean r=0.9996) over a concentration range of 25-3651ng/mL using a (1/x)-weighted scheme. Limit of detection and lower limit of quantitation were 10.6 and 25ng/mL, respectively. Overall accuracy Er (%) was ranging from -5.10% to 10.5%. Within- and between-run RSD (%) were lower 4.51% and 2.15%, respectively. Overall recovery of Bu was equal to 69.3±4.56% (RSD (%)). The present method is sensitive and specific, requiring a simple sample preparation procedure and short analysis time, advantages crucial for therapeutic drug monitoring of Bu in clinical practice and application in pharmacokinetic studies.
• Journal of pharmaceutical and biomedical analysis.J Pharm Biomed Anal.2014 Mar;90:207-14. doi: 10.1016/j.jpba.2013.12.004. Epub 2013 Dec 14.
• A simplified gas chromatographic-mass spectrometric (GC-MS) analytical method, involving a novel derivatization procedure was developed for monitoring busulfan (Bu) plasma concentrations in populations undergoing bone marrow transplantation. Plasma samples (500μL) containing Bu-d8 as internal stand
• PMID 24389463

• The histone deacetylase inhibitor SAHA sensitizes acute myeloid leukemia cells to a combination of nucleoside analogs and the DNA-alkylating agent busulfan.

• Song G, Valdez BC, Li Y, Dominguez JR, Corn P, Champlin RE, Andersson BS.Author information Department of Stem Cell Transplantation and Cellular Therapy, University of Texas M. D. Anderson Cancer Center , Houston, TX , USA.AbstractFludarabine (Flu), clofarabine (Clo) and busulfan (Bu) are used in allogeneic hematopoietic stem cell transplant (allo-HSCT). We reported that combining [Flu + Clo + Bu] had a synergistic cytotoxicity in AML cells. We hypothesized that combining [Flu + Clo + Bu] with the histone deacetylase inhibitor SAHA will further enhance cytotoxicity. We exposed the acute myeloid leukemia (AML) cell lines KBM3/Bu2506 and OCI-AML3 to Flu, Clo, Bu and SAHA alone and in various combinations. [Flu + Clo + Bu + SAHA] resulted in synergistic cytotoxicity, which can be attributed to (1) activated DNA-damage response and cell cycle checkpoint activation through the ATM-CHK2-P53 (or P73) pathway or ATM-CHK2-cdc25-cdc2 pathway, (2) histone modifications and (3) activated apoptosis pathway. The [Flu + Clo + Bu + SAHA] combination causes mitochondrial outer membrane permeabilization, leakage of cytochrome c and Smac/Diablo into the cytosol with caspase activation, and release of apoptosis-inducing factor (AIF) into the nucleus resulting in nuclear fragmentation and cell death. These results provide a mechanistic basis for using SAHA in future clinical trials with double nucleoside analog-busulfan combinations in pretransplant conditioning therapy.
• Leukemia & lymphoma.Leuk Lymphoma.2014 Feb 4. [Epub ahead of print]
• Fludarabine (Flu), clofarabine (Clo) and busulfan (Bu) are used in allogeneic hematopoietic stem cell transplant (allo-HSCT). We reported that combining [Flu + Clo + Bu] had a synergistic cytotoxicity in AML cells. We hypothesized that combining [Flu + Clo + Bu] with the histone deacetylase inhibito
• PMID 24144307

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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