Details of the Drug

General Information of Drug (ID: DMXYJ9C)

• Drug Name: Busulfan
• Synonyms: Busulfano; Busulfanum; Busulfex; Busulphan; Busulphane; Butanedioldimethanesulfonate; Buzulfan; Citosulfan; Glyzophrol; Leucosulfan; Mablin; Methanesulfonic; Mielevcin; Mielosan; Mielucin; Milecitan; Mileran; Misulban; Mitosan; Mitostan; Myeleukon; Myeloleukon; Myelosan; Myelosanum; Mylecytan; Myleran; Mylerlan; Sulfabutin; Sulphabutin; Busulfan GlaxoSmithKline Brand; Busulfan Orphan Brand; Busulfan Wellcome; Busulfan Wellcome Brand; Glaxo Wellcome Brand of Busulfan; GlaxoSmithKline Brand of Busulfan; Myleran tablets; Orphan Brand of Busulfan; Tetramethylene bis[methanesulfonate]; Tetramethylene dimethane sulfonate; Tetramethylenester kyseliny methansulfonove; Tetramethylenester kyseliny methansulfonove[Czech]; Wellcome Brand of Busulfan; AN 33501; CB 2041; GT 2041; GT 41; X 149; Acid, tetramethylene ester; Alkylating agent: crosslinks guanine residues; Busulfan [INN:JAN]; Busulfano [INN-Spanish]; Busulfanum [INN-Latin]; MYLERAN (TN); Methanesulfonic acid, tetram ethylene ester; Methanesulfonic acid, tetramethylene ester; Myleran (TN); Sulfabutin (VAN); Tetramethylene bis(methanesulfonate); Tetramethylene {bis[methanesulfonate]}; Wellcome, Busulfan; C.B. 2041; G.T. 41; Myleran, Busulfex, Busulfan; Busulfan (JP15/USP/INN); Butane-1,4-diyl dimethanesulfonate; BUSULFAN (1,4-BUTANEDIOL, DIMETHANESULFONATE); N-Butane-1,3-di(methylsulfonate); 1,4-BUTANEDIOL DIMETHANESULFONATE; 1,4-Bis(methanesulfonoxy)butane; 1,4-Bis(methanesulfonyloxy)butane; 1,4-Bis[methanesulfonoxy]butane; 1,4-Butanedi yl dimethanesulfonate; 1,4-Butanediol dimethanesulphonate; 1,4-Butanediol dimethylsulfonate; 1,4-Butanediol, dimethanesulfonate; 1,4-Butanediol, dimethanesulphonate; 1,4-Butanediyl dimethanesulfonate; 1,4-Di(methylsulfonoxy)butane; 1,4-Dimesyloxybutane; 1,4-Dimethane sulfonyl oxybutane; 1,4-Dimethanesulfonoxybutane; 1,4-Dimethanesulfonoxylbutane; 1,4-Dimethanesulfonyloxybutane; 1,4-Dimethanesulphonyloxybutane; 1,4-Dimethylsulfonoxybutane; 1,4-Dimethylsulfonyloxybutane; 1,{4-Bis[methanesulfonoxy]butane}; 4-((Methylsulfonyl)oxy)butyl methanesulfonate; 4-methylsulfonyloxybutyl methanesulfonate

Indication

Disease Entry	ICD 11	Status	REF
Chronic myelogenous leukaemia	2A20.0	Approved	[1]
Hematologic disease	3C0Z	Approved	[1]
Immunodeficiency	4A00-4A85	Approved	[1]
Leukemia	N.A.	Approved	[1]
Myeloproliferative syndrome	2A22	Approved	[2]
Systemic lupus erythematosus	4A40.0	Approved	[1]
Systemic sclerosis	4A42	Approved	[1]
Neuroblastoma	2D11.2	Investigative	[1]
Retinoblastoma	2D02.2	Investigative	[1]

• Therapeutic Class: Anticancer Agents
• Affected Organisms: Humans and other mammals
• ATC Code:
  L01AB01: Busulfan
  L01AB: Alkyl sulfonates
  L01A: ALKYLATING AGENTS
  L01: ANTINEOPLASTIC AGENTS
  L: ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS
• Drug Type: Small molecular drug
• #Ro5 Violations (Lipinski): 0:
  Molecular Weight (mw); 246.3
  Logarithm of the Partition Coefficient (xlogp); -0.5
  Rotatable Bond Count (rotbonds); 7
  Hydrogen Bond Donor Count (hbonddonor); 0
  Hydrogen Bond Acceptor Count (hbondacc); 6
• ADMET Property:
  BDDCS Class: Biopharmaceutics Drug Disposition Classification System (BDDCS) Class 1: high solubility and high permeability [3]
  Bioavailability: 70% of drug becomes completely available to its intended biological destination(s) [4]
  Clearance: The drug present in the plasma can be removed from the body at the rate of 2.4 mL/min/kg [5]
  Elimination: 1% of drug is excreted from urine in the unchanged form [3]
  Half-life: The concentration or amount of drug in body reduced by one-half in 2.6 hours [5]
  Metabolism: The drug is metabolized via the hepatic []
  MRTD: The Maximum Recommended Therapeutic Dose (MRTD) of drug that ensured maximising efficacy and moderate side effect is 0.232 micromolar/kg/day [6]
  Unbound Fraction: The unbound fraction of drug in plasma is 1% [5]
  Vd: Fluid volume that would be required to contain the amount of drug present in the body at the same concentration as in the plasma 0.55 L/kg [5]
  Water Solubility: The ability of drug to dissolve in water is measured as 0.1 mg/mL [3]
• Chemical Identifiers:
  Formula: C6H14O6S2
  IUPAC Name: 4-methylsulfonyloxybutyl methanesulfonate
  Canonical SMILES: CS(=O)(=O)OCCCCOS(=O)(=O)C
  InChI: InChI=1S/C6H14O6S2/c1-13(7,8)11-5-3-4-6-12-14(2,9)10/h3-6H2,1-2H3
  InChIKey: COVZYZSDYWQREU-UHFFFAOYSA-N
• Cross-matching ID:
  PubChem CID: 2478
  ChEBI ID: CHEMBL820
  CAS Number: 55-98-1
  UNII: G1LN9045DK
  DrugBank ID: DB01008
  TTD ID: D07SUG
  INTEDE ID: DR0249
  ACDINA ID: D00085
• Drug-Molecule Activity Atlas (DMA)NEW: Click to Jump to the Detailed DMA Information of This Drug
• Drug Pharmacogenomic Perturbation (DPP)NEW: Click to Jump to the Detailed DPP Information of This Drug
• Drug ADMET Endpoint Profile (DAE)NEW: Click to Jump to the Detailed DAE Information of This Drug
• Repurposed Drugs (RPD): Click to Jump to the Detailed RPD Information of This Drug

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Human Deoxyribonucleic acid (hDNA)	TTUTN1I	NOUNIPROTAC	Modulator	[7]

Drug-Metabolizing Enzyme (DME)

DME Name	DME ID	UniProt ID	MOA	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Substrate	[8]
Glutathione S-transferase alpha-1 (GSTA1)	DE4ZHS1	GSTA1_HUMAN	Substrate	[9]
Glutathione S-transferase pi (GSTP1)	DEK6079	GSTP1_HUMAN	Substrate	[10]
Glutathione S-transferase mu-1 (GSTM1)	DEYZEJA	GSTM1_HUMAN	Substrate	[10]
Microsomal glutathione S-transferase 2 (MGST2)	DE31KMQ	MGST2_HUMAN	Substrate	[11]
Glutathione S-transferase alpha-2 (GSTA2)	DEH49YS	GSTA2_HUMAN	Substrate	[12]

Drug Off-Target (DOT)

DOT Name	DOT ID	UniProt ID	Interaction	REF
Antithrombin-III (SERPINC1)	OTDFATG0	ANT3_HUMAN	Gene/Protein Processing	[13]
Cyclic AMP-dependent transcription factor ATF-4 (ATF4)	OTRFV19J	ATF4_HUMAN	Gene/Protein Processing	[14]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Gene/Protein Processing	[15]
DNA repair nuclease/redox regulator APEX1 (APEX1)	OT53OI14	APEX1_HUMAN	Drug Response	[16]
Histone H2AX (H2AX)	OT18UX57	H2AX_HUMAN	Post-Translational Modifications	[17]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Gene/Protein Processing	[15]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Gene/Protein Processing	[15]
Nuclear factor NF-kappa-B p105 subunit (NFKB1)	OTNRRD8I	NFKB1_HUMAN	Gene/Protein Processing	[14]
Plasminogen activator inhibitor 1 (SERPINE1)	OTT0MPQ3	PAI1_HUMAN	Gene/Protein Processing	[18]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Protein Interaction/Cellular Processes	[17]

Drug-Drug Interaction (DDI) Information of This Drug

Coadministration of a Drug Treating the Same Disease as Busulfan

DDI Drug Name	DDI Drug ID	Severity	Mechanism	Disease	REF
Nilotinib	DM7HXWT	Moderate	Decreased metabolism of Busulfan caused by Nilotinib mediated inhibition of CYP450 enzyme.	Myeloproliferative neoplasm [2A20]	[19]
Omacetaxine mepesuccinate	DMPU2WX	Moderate	Additive myelosuppressive effects by the combination of Busulfan and Omacetaxine mepesuccinate.	Myeloproliferative neoplasm [2A20]	[20]

Coadministration of a Drug Treating the Disease Different from Busulfan (Comorbidity)

DDI Drug Name	DDI Drug ID	Severity	Mechanism	Comorbidity	REF
Dronedarone	DMA8FS5	Moderate	Decreased metabolism of Busulfan caused by Dronedarone mediated inhibition of CYP450 enzyme.	Angina pectoris [BA40]	[21]
Roflumilast	DMPGHY8	Moderate	Additive immunosuppressive effects by the combination of Busulfan and Roflumilast.	Asthma [CA23]	[22]
Ofloxacin	DM0VQN3	Minor	Decreased absorption of Busulfan due to intestinal mucosa variation caused by Ofloxacin.	Bacterial infection [1A00-1C4Z]	[23]
Sparfloxacin	DMB4HCT	Minor	Decreased absorption of Busulfan due to intestinal mucosa variation caused by Sparfloxacin.	Bacterial infection [1A00-1C4Z]	[23]
Gemifloxacin	DMHT34O	Minor	Decreased absorption of Busulfan due to intestinal mucosa variation caused by Gemifloxacin.	Bacterial infection [1A00-1C4Z]	[23]
Norfloxacin	DMIZ6W2	Minor	Decreased absorption of Busulfan due to intestinal mucosa variation caused by Norfloxacin.	Bacterial infection [1A00-1C4Z]	[23]
ABT-492	DMJFD2I	Minor	Decreased absorption of Busulfan due to intestinal mucosa variation caused by ABT-492.	Bacterial infection [1A00-1C4Z]	[23]
Levofloxacin	DMS60RB	Minor	Decreased absorption of Busulfan due to intestinal mucosa variation caused by Levofloxacin.	Bacterial infection [1A00-1C4Z]	[23]
Lapatinib	DM3BH1Y	Moderate	Decreased metabolism of Busulfan caused by Lapatinib mediated inhibition of CYP450 enzyme.	Breast cancer [2C60-2C6Y]	[24]
Ivacaftor	DMZC1HS	Moderate	Decreased metabolism of Busulfan caused by Ivacaftor mediated inhibition of CYP450 enzyme.	Cystic fibrosis [CA25]	[25]
Stiripentol	DMMSDOY	Moderate	Decreased metabolism of Busulfan caused by Stiripentol mediated inhibition of CYP450 enzyme.	Epilepsy/seizure [8A61-8A6Z]	[26]
Rufinamide	DMWE60C	Moderate	Increased metabolism of Busulfan caused by Rufinamide mediated induction of CYP450 enzyme.	Epilepsy/seizure [8A61-8A6Z]	[22]
Miconazole	DMPMYE8	Moderate	Decreased metabolism of Busulfan caused by Miconazole mediated inhibition of CYP450 enzyme.	Fungal infection [1F29-1F2F]	[22]
Boceprevir	DMBSHMF	Moderate	Decreased metabolism of Busulfan caused by Boceprevir mediated inhibition of CYP450 enzyme.	Hepatitis virus infection [1E50-1E51]	[27]
Telaprevir	DMMRV29	Moderate	Decreased metabolism of Busulfan caused by Telaprevir mediated inhibition of CYP450 enzyme.	Hepatitis virus infection [1E50-1E51]	[28]
Etravirine	DMGV8QU	Moderate	Increased metabolism of Busulfan caused by Etravirine mediated induction of CYP450 enzyme.	Human immunodeficiency virus disease [1C60-1C62]	[29]
Teriflunomide	DMQ2FKJ	Major	Additive myelosuppressive effects by the combination of Busulfan and Teriflunomide.	Hyper-lipoproteinaemia [5C80]	[30]
Denosumab	DMNI0KO	Moderate	Additive immunosuppressive effects by the combination of Busulfan and Denosumab.	Low bone mass disorder [FB83]	[31]
Brigatinib	DM7W94S	Moderate	Increased metabolism of Busulfan caused by Brigatinib mediated induction of CYP450 enzyme.	Lung cancer [2C25]	[32]
Dabrafenib	DMX6OE3	Moderate	Increased metabolism of Busulfan caused by Dabrafenib mediated induction of CYP450 enzyme.	Melanoma [2C30]	[22]
Thalidomide	DM70BU5	Major	Additive thrombogenic effects by the combination of Busulfan and Thalidomide.	Multiple myeloma [2A83]	[33]
Tecfidera	DM2OVDT	Moderate	Additive immunosuppressive effects by the combination of Busulfan and Tecfidera.	Multiple sclerosis [8A40]	[34]
Siponimod	DM2R86O	Major	Additive immunosuppressive effects by the combination of Busulfan and Siponimod.	Multiple sclerosis [8A40]	[35]
Fingolimod	DM5JVAN	Major	Additive immunosuppressive effects by the combination of Busulfan and Fingolimod.	Multiple sclerosis [8A40]	[36]
Ocrelizumab	DMEZ2KH	Moderate	Additive immunosuppressive effects by the combination of Busulfan and Ocrelizumab.	Multiple sclerosis [8A40]	[37]
Ozanimod	DMT6AM2	Major	Additive immunosuppressive effects by the combination of Busulfan and Ozanimod.	Multiple sclerosis [8A40]	[22]
Temsirolimus	DMS104F	Moderate	Increased plasma concentrations of Busulfan and Temsirolimus due to competitive inhibition of the same metabolic pathway.	Renal cell carcinoma [2C90]	[38]
Gatifloxacin	DMSL679	Minor	Decreased absorption of Busulfan due to intestinal mucosa variation caused by Gatifloxacin.	Respiratory infection [CA07-CA4Z]	[23]
Canakinumab	DM8HLO5	Moderate	Additive immunosuppressive effects by the combination of Busulfan and Canakinumab.	Rheumatoid arthritis [FA20]	[39]
Rilonacept	DMGLUQS	Moderate	Additive immunosuppressive effects by the combination of Busulfan and Rilonacept.	Rheumatoid arthritis [FA20]	[39]
Golimumab	DMHZV7X	Major	Additive immunosuppressive effects by the combination of Busulfan and Golimumab.	Rheumatoid arthritis [FA20]	[40]
Anthrax vaccine	DM9GSWY	Moderate	Antagonize the effect of Busulfan when combined with Anthrax vaccine.	Sepsis [1G40-1G41]	[41]
Armodafinil	DMGB035	Minor	Increased metabolism of Busulfan caused by Armodafinil mediated induction of CYP450 enzyme.	Solid tumour/cancer [2A00-2F9Z]	[42]
Valganciclovir	DMS2IUH	Moderate	Additive myelosuppressive effects by the combination of Busulfan and Valganciclovir.	Virus infection [1A24-1D9Z]	[35]

Drug Inactive Ingredient(s) (DIG) and Formulation(s) of This Drug

DIG

DIG Name	DIG ID	PubChem CID	Functional Classification
Beta-D-lactose	E00099	6134	Diluent; Dry powder inhaler carrier; Lyophilization aid
Magnesium stearate	E00208	11177	lubricant
Titanium dioxide	E00322	26042	Coating agent; Colorant; Opacifying agent
Triacetin	E00080	5541	Humectant; Plasticizing agent; Solvent

Pharmaceutical Formulation

Formulation Name	Drug Dosage	Dosage Form	Route
Busulfan 2 mg tablet	2 mg	Oral Tablet	Oral

Jump to Detail Pharmaceutical Formulation Page of This Drug

References

• [1] Busulfan FDA Label
• [2] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7136).
• [3] BDDCS applied to over 900 drugs
• [4] Critical Evaluation of Human Oral Bioavailability for Pharmaceutical Drugs by Using Various Cheminformatics Approaches
• [5] Trend Analysis of a Database of Intravenous Pharmacokinetic Parameters in Humans for 1352 Drug Compounds
• [6] Estimating the safe starting dose in phase I clinical trials and no observed effect level based on QSAR modeling of the human maximum recommended daily dose
• [7] DNA intrastrand cross-link at the 5'-GA-3' sequence formed by busulfan and its role in the cytotoxic effect. Cancer Sci. 2004 May;95(5):454-8.
• [8] Update: clinically significant cytochrome P-450 drug interactions. Pharmacotherapy. 1998 Jan-Feb;18(1):84-112.
• [9] Glutathione S-transferase M1 polymorphism: a risk factor for hepatic venoocclusive disease in bone marrow transplantation. Blood. 2004 Sep 1;104(5):1574-7.
• [10] Busulfan conjugation by glutathione S-transferases alpha, mu, and pi. Drug Metab Dispos. 1996 Sep;24(9):1015-9.
• [11] Overexpression of glutathione-S-transferase, MGSTII, confers resistance to busulfan and melphalan. Cancer Invest. 2005;23(1):19-25.
• [12] Endothelial cells do not express GSTA1: potential relevance to busulfan-mediated endothelial damage during haematopoietic stem cell transplantation. Eur J Haematol. 2008 Apr;80(4):299-302.
• [13] Decreased incidence of hepatic veno-occlusive disease and fewer hemostatic derangements associated with intravenous busulfan vs oral busulfan in adults conditioned with busulfan + cyclophosphamide for allogeneic bone marrow transplantation. Ann Hematol. 2005 May;84(5):321-30. doi: 10.1007/s00277-004-0982-4. Epub 2004 Dec 4.
• [14] Direct transcriptomic comparison of xenobiotic metabolism and toxicity pathway induction of airway epithelium models at an air-liquid interface generated from induced pluripotent stem cells and primary bronchial epithelial cells. Cell Biol Toxicol. 2023 Feb;39(1):1-18. doi: 10.1007/s10565-022-09726-0. Epub 2022 May 31.
• [15] Busulfan selectively induces cellular senescence but not apoptosis in WI38 fibroblasts via a p53-independent but extracellular signal-regulated kinase-p38 mitogen-activated protein kinase-dependent mechanism. J Pharmacol Exp Ther. 2006 Nov;319(2):551-60. doi: 10.1124/jpet.106.107771. Epub 2006 Aug 1.
• [16] Impairment of APE1 function enhances cellular sensitivity to clinically relevant alkylators and antimetabolites. Mol Cancer Res. 2009 Jun;7(6):897-906. doi: 10.1158/1541-7786.MCR-08-0519. Epub 2009 May 26.
• [17] Altered gene expression in busulfan-resistant human myeloid leukemia. Leuk Res. 2008 Nov;32(11):1684-97. doi: 10.1016/j.leukres.2008.01.016. Epub 2008 Mar 12.
• [18] Antineoplastic agent busulfan regulates a network of genes related to coagulation and fibrinolysis. Eur J Clin Pharmacol. 2012 Jun;68(6):923-35. doi: 10.1007/s00228-011-1209-y.
• [19] Product Information. Tasigna (nilotinib). Novartis Pharmaceuticals, East Hanover, NJ.
• [20] Product Information. Synribo (omacetaxine). Teva Pharmaceuticals USA, North Wales, PA.
• [21] Product Information. Multaq (dronedarone). sanofi-aventis , Bridgewater, NJ.
• [22] Cerner Multum, Inc. "UK Summary of Product Characteristics.".
• [23] Johnson EJ, MacGowan AP, Potter MN, et al "Reduced absorption of oral ciprofloxacin after chemotherapy for haematological malignancy." J Antimicrob Chemother 25 (1990): 837-42. [PMID: 2373666]
• [24] Product Information. Tykerb (lapatinib). Novartis Pharmaceuticals, East Hanover, NJ.
• [25] Product Information. Kalydeco (ivacaftor). Vertex Pharmaceuticals, Cambridge, MA.
• [26] EMEA. European Medicines Agency "EPARs. European Union Public Assessment Reports.".
• [27] Product Information. Victrelis (boceprevir). Schering-Plough Corporation, Kenilworth, NJ.
• [28] Product Information. Incivek (telaprevir). Vertex Pharmaceuticals, Cambridge, MA.
• [29] Product Information. Intelence (etravirine). Ortho Biotech Inc, Bridgewater, NJ.
• [30] Product Information. Arava (leflunomide). Hoechst Marion-Roussel Inc, Kansas City, MO.
• [31] Product Information. Prolia (denosumab). Amgen USA, Thousand Oaks, CA.
• [32] Product Information. Alunbrig (brigatinib). Ariad Pharmaceuticals Inc, Cambridge, MA.
• [33] Bennett CL, Nebeker JR, Samore MH, et al "The Research on Adverse Drug Events and Reports (RADAR) project." JAMA 293 (2005): 2131-40. [PMID: 15870417]
• [34] Product Information. Vumerity (diroximel fumarate). Alkermes, Inc, Cambridge, MA.
• [35] Cerner Multum, Inc. "Australian Product Information.".
• [36] Product Information. Gilenya (fingolimod). Novartis Pharmaceuticals, East Hanover, NJ.
• [37] Product Information. Ocrevus (ocrelizumab). Genentech, South San Francisco, CA.
• [38] Product Information. Prograf (tacrolimus). Fujisawa, Deerfield, IL.
• [39] Product Information. Arcalyst (rilonacept). Regeneron Pharmaceuticals Inc, Tarrytown, NY.
• [40] Product Information. Cimzia (certolizumab). UCB Pharma Inc, Smyrna, GA.
• [41] CDC. Centers for Disease Control and Prevention/ "Recommendations of the advisory committtee on immunization practices (ACIP): use of vaccines and immune globulins in persons with altered immunocompetence." MMWR Morb Mortal Wkly Rep 42(RR-04) (1993): 1-18. [PMID: 20300058]
• [42] Doherty MM, Charman WN "The mucosa of the small intestine: how clinically relevant as an organ of drug metabolism?" Clin Pharmacokinet 41 (2002): 235-53. [PMID: 11978143]