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Identification
NameCyclophosphamide
Accession NumberDB00531  (APRD00408)
Typesmall molecule
Groupsapproved, investigational
Description

Precursor of an alkylating nitrogen mustard antineoplastic and immunosuppressive agent that must be activated in the liver to form the active aldophosphamide. It has been used in the treatment of lymphoma and leukemia. Its side effect, alopecia, has been used for defleecing sheep. Cyclophosphamide may also cause sterility, birth defects, mutations, and cancer. [PubChem]

Structure
Thumb
Synonyms
SynonymLanguageCode
(+-)-CyclophosphamideNot AvailableNot Available
(RS)-CyclophosphamideNot AvailableNot Available
CiclofosfamidaSpanishINN
CiclofosfamideNot AvailableIS
CyclophosphamidGermanINN
CyclophosphamideFrenchINN
Cyclophosphamide anhydrousNot AvailableNot Available
CyclophosphamidumLatinINN
CytophosphaneNot AvailableNot Available
LedoxinaNot AvailableIS
SaltsNot Available
Brand names
NameCompany
CytoxanBristol-Myers Squibb
EndoxanActavis
NeosarNot Available
ProcytoxBaxter
RevimmuneNot Available
SendoxanBaxter
Brand mixturesNot Available
Categories
CAS number50-18-0
WeightAverage: 261.086
Monoisotopic: 260.02481966
Chemical FormulaC7H15Cl2N2O2P
InChI KeyInChIKey=CMSMOCZEIVJLDB-UHFFFAOYSA-N
InChI
InChI=1S/C7H15Cl2N2O2P/c8-2-5-11(6-3-9)14(12)10-4-1-7-13-14/h1-7H2,(H,10,12)
IUPAC Name
2-[bis(2-chloroethyl)amino]-1,3,2$l^{5}-oxazaphosphinan-2-one
SMILES
ClCCN(CCCl)P1(=O)NCCCO1
Mass Specshow(9.91 KB)
Taxonomy
KingdomOrganic Compounds
SuperclassOrganonitrogen Compounds
ClassAmines
SubclassTertiary Amines
Direct parentNitrogen Mustard Compounds
Alternative parentsPhosphorodiamides; Oxazaphosphinanes; Organophosphate Esters; Polyamines; Organochlorides; Alkyl Chlorides
Substituentsphosphorodiamide; phosphoric acid ester; oxazaphosphinane; polyamine; organochloride; organohalogen; alkyl halide; alkyl chloride
Classification descriptionThis compound belongs to the nitrogen mustard compounds. These are compounds having two beta-haloalkyl groups bound to a phosphorus atom.
Pharmacology
IndicationCyclophosphamide is indicated for the treatment of malignant lymphomas, multiple myeloma, leukemias, mycosis fungoides (advanced disease), neuroblastoma (disseminated disease), adenocarcinoma of the ovary, retinoblastoma, and carcinoma of the breast. It is also indicated for the treatment of biopsy-proven minimal change nephrotic syndrome in pediatric patients.
PharmacodynamicsCyclophosphamide is an antineoplastic in the class of alkylating agents and is used to treat various forms of cancer. Alkylating agents are so named because of their ability to add alkyl groups to many electronegative groups under conditions present in cells. They stop tumor growth by cross-linking guanine bases in DNA double-helix strands - directly attacking DNA. This makes the strands unable to uncoil and separate. As this is necessary in DNA replication, the cells can no longer divide. In addition, these drugs add methyl or other alkyl groups onto molecules where they do not belong which in turn inhibits their correct utilization by base pairing and causes a miscoding of DNA. Alkylating agents are cell cycle-nonspecific. Alkylating agents work by three different mechanisms all of which achieve the same end result - disruption of DNA function and cell death.
Mechanism of actionAlkylating agents work by three different mechanisms: 1) attachment of alkyl groups to DNA bases, resulting in the DNA being fragmented by repair enzymes in their attempts to replace the alkylated bases, preventing DNA synthesis and RNA transcription from the affected DNA, 2) DNA damage via the formation of cross-links (bonds between atoms in the DNA) which prevents DNA from being separated for synthesis or transcription, and 3) the induction of mispairing of the nucleotides leading to mutations.
AbsorptionAfter oral administration, peak concentrations occur at one hour.
Volume of distribution

30-50 L

Protein binding20% of cyclophosphamide is protein bound with no dose dependent changes. Some metabolites are protein bound to an extent greater than 60%.
Metabolism

Metabolism and activation occurs at the liver. 75% of the drug is activated by cytochrome P450 isoforms, CYP2A6, 2B6, 3A4, 3A5, 2C9, 2C18, and 2C19. The CYP2B6 isoform is the enzyme with the highest 4-hydroxylase activity. Cyclophosphamide undergoes activation to eventually form active metabolites, phosphoramide mustard and acrolein. Cyclophosphamide appears to induce its own metabolism which results in an overall increase in clearance, increased formation of 4-hydroxyl metabolites, and shortened t1/2 values following repeated administration.

SubstrateEnzymesProduct
Cyclophosphamide
4-HydroxycyclophosphamideDetails
Cyclophosphamide
Dechloroethyl cyclophosphamideDetails
Cyclophosphamide
ChloroacetaldehydeDetails
4-Hydroxycyclophosphamide
4-KetocyclophosphamideDetails
4-Hydroxycyclophosphamide
    AldophosphamideDetails
    Aldophosphamide
      CarboxyphosphamideDetails
      Aldophosphamide
      AlcophosphamideDetails
      Aldophosphamide
      CarboxyphosphamideDetails
      Carboxyphosphamide
        Nornitrogen mustardDetails
        Aldophosphamide
          AcroleinDetails
          Acrolein
          Acrylic AcidDetails
          Aldophosphamide
            Phosphoramide MustardDetails
            Phosphoramide Mustard
              Phosphoramide AziridiniumDetails
              Route of eliminationCyclophosphamide is eliminated primarily in the form of metabolites. 10-20% is excreted unchanged in the urine and 4% is excreted in the bile following IV administration.
              Half life3-12 hours
              Clearance

              Total body clearance = 63 ± 7.6 L/kg.

              ToxicityAdverse reactions reported most often include neutropenia, febrile neutropenia, fever, alopecia, nausea, vomiting, and diarrhea.
              Affected organisms
              • Humans and other mammals
              Pathways
              PathwayCategorySMPDB ID
              Cyclophosphamide Action PathwayDrug actionSMP00447
              Cyclophosphamide Metabolism PathwayDrug metabolismSMP00604
              SNP Mediated Effects
              Interacting Gene/EnzymeSNP RS IDAllele nameDefining changeEffectReference(s)
              Cytochrome P450 3A4
              Gene symbol: CYP3A4
              UniProt: P08684
              rs2740574 CYP3A4 *1BG AllelleDecreased activation of cyclophosphamide most likely contributing to worse disease free survival in adjuvant chemotherapy for node-positive breast cancer20459744
              Cytochrome P450 2B6
              Gene symbol: CYP2B6
              UniProt: P20813
              Not AvailableCYP2B6*1GC AllelleDecreased activation of cyclophosphamide contributing to less adverse reactions (leukocytopenia)17502835
              SNP Mediated Adverse Drug ReactionsNot Available
              ADMET
              Predicted ADMET features
              Property Value Probability
              Human Intestinal Absorption + 0.9722
              Blood Brain Barrier + 0.971
              Caco-2 permeable - 0.5451
              P-glycoprotein substrate Non-substrate 0.71
              P-glycoprotein inhibitor I Non-inhibitor 0.779
              P-glycoprotein inhibitor II Non-inhibitor 0.9797
              Renal organic cation transporter Non-inhibitor 0.8125
              CYP450 2C9 substrate Non-substrate 0.7856
              CYP450 2D6 substrate Non-substrate 0.5884
              CYP450 3A4 substrate Substrate 0.5461
              CYP450 1A2 substrate Non-inhibitor 0.9045
              CYP450 2C9 substrate Non-inhibitor 0.9071
              CYP450 2D6 substrate Non-inhibitor 0.9232
              CYP450 2C19 substrate Non-inhibitor 0.9026
              CYP450 3A4 substrate Non-inhibitor 0.9232
              CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.9737
              Ames test AMES toxic 0.9146
              Carcinogenicity Non-carcinogens 0.8727
              Biodegradation Not ready biodegradable 0.9511
              Rat acute toxicity 3.3855 LD50, mol/kg Not applicable
              hERG inhibition (predictor I) Strong inhibitor 0.8419
              hERG inhibition (predictor II) Non-inhibitor 0.8735
              Pharmacoeconomics
              Manufacturers
              • Baxter healthcare corp
              • Baxter healthcare corp anesthesia and critical care
              • Teva parenteral medicines inc
              • Roxane laboratories inc
              Packagers
              Dosage forms
              FormRouteStrength
              Injection, powder, for solutionIntravenous200 mg, 500 mg, 1 g, 2 g
              TabletOral25 mg, 50 mg
              Prices
              Unit descriptionCostUnit
              Cyclophosphamide 500 mg vial37.76USDvial
              Cyclophosphamide 100% powder33.66USDg
              Cytoxan 500 mg vial15.25USDvial
              Cytoxan 50 mg tablet4.14USDtablet
              Cyclophosphamide 50 mg tablet3.92USDtablet
              Cytoxan 25 mg tablet2.26USDtablet
              Cyclophosphamide 25 mg tablet2.09USDtablet
              DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
              PatentsNot Available
              Properties
              Statesolid
              Experimental Properties
              PropertyValueSource
              melting point41-45 °CNot Available
              water solubilitySoluble. 1-5 g/100 mL at 23 °CNot Available
              logP0.8Not Available
              Predicted Properties
              PropertyValueSource
              water solubility1.51e+01 g/lALOGPS
              logP0.76ALOGPS
              logP0.097ChemAxon
              logS-1.2ALOGPS
              pKa (strongest acidic)12.78ChemAxon
              pKa (strongest basic)-0.57ChemAxon
              physiological charge0ChemAxon
              hydrogen acceptor count2ChemAxon
              hydrogen donor count1ChemAxon
              polar surface area41.57ChemAxon
              rotatable bond count5ChemAxon
              refractivity58.48ChemAxon
              polarizability23.72ChemAxon
              number of rings1ChemAxon
              bioavailability1ChemAxon
              rule of fiveYesChemAxon
              Ghose filterYesChemAxon
              Veber's ruleNoChemAxon
              MDDR-like ruleNoChemAxon
              Spectra
              SpectraNot Available
              References
              Synthesis Reference

              Riccardo Dalla-Favera, Alessandro Massimo Gianni, “Retroviral vector capable of transducing the aldehyde dehydrogenase-1 gene and making cells resistant to the chemotherapeutic agent cyclophosphamide and its derivatives and analogs.” U.S. Patent US6268138, issued March, 1999.

              US6268138
              General Reference
              1. Brock N: The history of the oxazaphosphorine cytostatics. Cancer. 1996 Aug 1;78(3):542-7. Pubmed
              2. Brock N: Oxazaphosphorine cytostatics: past-present-future. Seventh Cain Memorial Award lecture. Cancer Res. 1989 Jan 1;49(1):1-7. Pubmed
              3. FDA label
              External Links
              ResourceLink
              KEGG DrugD07760
              KEGG CompoundC07888
              PubChem Compound2907
              PubChem Substance46505441
              ChemSpider2804
              ChEBI4027
              ChEMBLCHEMBL88
              Therapeutic Targets DatabaseDAP000532
              PharmGKBPA449165
              Drug Product Database2241797
              RxListhttp://www.rxlist.com/cgi/generic3/cyclophosphamide.htm
              Drugs.comhttp://www.drugs.com/cdi/cyclophosphamide.html
              PDRhealthhttp://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/cyt1112.shtml
              WikipediaCyclophosphamide
              ATC CodesL01AA01L01DB07
              AHFS Codes
              • 10:00.00
              PDB EntriesNot Available
              FDA labelNot Available
              MSDSshow(76.1 KB)
              Interactions
              Drug Interactions
              Drug
              AcenocoumarolThe antineoplastic agent, cyclophosphamide may alter the anticoagulant effect of acenocoumarol.
              AnisindioneThe antineoplastic agent, cyclophosphamide may alter the anticoagulant effect of anisindione.
              BendamustineIncreases toxicity through pharmacodynamic synergism. Additive myelosuppression.
              DicoumarolThe antineoplastic agent, cyclophosphamide may alter the anticoagulant effect of dicumarol.
              DigoxinThe antineoplasic agent decreases the effect of digoxin
              FluconazoleFluconazole reduces metabolism and clearance of cyclophosphamide.
              PentostatinIncreased toxicity of cyclophosphamide
              SuccinylcholineCyclophosphamide may increase the effect of succinylcholine.
              ThiotepaThiotepa, a strong CYP2B6 inhibitor, may decrease the metabolism and clearance of Cyclophosphamide, a CYP2B6 substrate. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Cyclophosphamide if Thiotepa is initiated, discontinued or dose changed.
              TrastuzumabTrastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events.
              WarfarinThe antineoplastic agent, cyclophosphamide may alter the anticoagulant effect of warfarin.
              Food Interactions
              • Drink liberally- 2 to 3 liters/day.
              • Take with food to reduce irritation.

              1. DNA

              Kind: nucleotide

              Organism: Human

              Pharmacological action: yes

              Actions: cross-linking/alkylation

              Components

              Name UniProt ID Details

              References:

              1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
              2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed
              3. Khan O, Middleton MR: The therapeutic potential of O6-alkylguanine DNA alkyltransferase inhibitors. Expert Opin Investig Drugs. 2007 Oct;16(10):1573-84. Pubmed
              4. Schmidt E, Tony HP, Brocker EB, Kneitz C: Sun-induced life-threatening lupus nephritis. Ann N Y Acad Sci. 2007 Jun;1108:35-40. Pubmed
              5. Zhang QH, Wu CF, Duan L, Yang JY: Protective effects of total saponins from stem and leaf of Panax ginseng against cyclophosphamide-induced genotoxicity and apoptosis in mouse bone marrow cells and peripheral lymphocyte cells. Food Chem Toxicol. 2007 Aug 23;. Pubmed

              1. Cytochrome P450 2C9

              Kind: protein

              Organism: Human

              Pharmacological action: unknown

              Actions: substrate inducer

              Components

              Name UniProt ID Details
              Cytochrome P450 2C9 P11712 Details

              References:

              1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed
              2. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

              2. Cytochrome P450 3A4

              Kind: protein

              Organism: Human

              Pharmacological action: unknown

              Actions: substrate inhibitor inducer

              Components

              Name UniProt ID Details
              Cytochrome P450 3A4 P08684 Details

              References:

              1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed
              2. Preiss R, Schmidt R, Baumann F, Hanschmann H, Hauss J, Geissler F, Pahlig H, Ratzewiss B: Measurement of 4-hydroxylation of ifosfamide in human liver microsomes using the estimation of free and protein-bound acrolein and codetermination of keto- and carboxyifosfamide. J Cancer Res Clin Oncol. 2002 Jul;128(7):385-92. Epub 2002 Jun 11. Pubmed
              3. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

              3. Cytochrome P450 2B6

              Kind: protein

              Organism: Human

              Pharmacological action: unknown

              Actions: substrate inducer

              Components

              Name UniProt ID Details
              Cytochrome P450 2B6 P20813 Details

              References:

              1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed
              2. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
              3. Preiss R, Schmidt R, Baumann F, Hanschmann H, Hauss J, Geissler F, Pahlig H, Ratzewiss B: Measurement of 4-hydroxylation of ifosfamide in human liver microsomes using the estimation of free and protein-bound acrolein and codetermination of keto- and carboxyifosfamide. J Cancer Res Clin Oncol. 2002 Jul;128(7):385-92. Epub 2002 Jun 11. Pubmed
              4. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

              4. Cytochrome P450 2C19

              Kind: protein

              Organism: Human

              Pharmacological action: unknown

              Actions: substrate

              Components

              Name UniProt ID Details
              Cytochrome P450 2C19 P33261 Details

              References:

              1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
              2. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

              5. Cytochrome P450 2A6

              Kind: protein

              Organism: Human

              Pharmacological action: unknown

              Actions: substrate

              Components

              Name UniProt ID Details
              Cytochrome P450 2A6 P11509 Details

              References:

              1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

              6. Cytochrome P450 2C18

              Kind: protein

              Organism: Human

              Pharmacological action: unknown

              Actions: substrate

              Components

              Name UniProt ID Details
              Cytochrome P450 2C18 P33260 Details

              References:

              1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

              7. Cytochrome P450 2C8

              Kind: protein

              Organism: Human

              Pharmacological action: unknown

              Actions: substrate inducer

              Components

              Name UniProt ID Details
              Cytochrome P450 2C8 P10632 Details

              References:

              1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

              8. Cytochrome P450 2D6

              Kind: protein

              Organism: Human

              Pharmacological action: unknown

              Actions: substrate

              Components

              Name UniProt ID Details
              Cytochrome P450 2D6 P10635 Details

              References:

              1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

              9. Cytochrome P450 3A7

              Kind: protein

              Organism: Human

              Pharmacological action: unknown

              Actions: substrate

              Components

              Name UniProt ID Details
              Cytochrome P450 3A7 P24462 Details

              References:

              1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

              10. Cytochrome P450 3A5

              Kind: protein

              Organism: Human

              Pharmacological action: unknown

              Actions: substrate

              Components

              Name UniProt ID Details
              Cytochrome P450 3A5 P20815 Details

              References:

              1. Ekhart C, Doodeman VD, Rodenhuis S, Smits PH, Beijnen JH, Huitema AD: Influence of polymorphisms of drug metabolizing enzymes (CYP2B6, CYP2C9, CYP2C19, CYP3A4, CYP3A5, GSTA1, GSTP1, ALDH1A1 and ALDH3A1) on the pharmacokinetics of cyclophosphamide and 4-hydroxycyclophosphamide. Pharmacogenet Genomics. 2008 Jun;18(6):515-23. doi: 10.1097/FPC.0b013e3282fc9766. Pubmed

              1. Multidrug resistance protein 1

              Kind: protein

              Organism: Human

              Pharmacological action: unknown

              Actions: inhibitor

              Components

              Name UniProt ID Details
              Multidrug resistance protein 1 P08183 Details

              References:

              1. Wang E, Lew K, Barecki M, Casciano CN, Clement RP, Johnson WW: Quantitative distinctions of active site molecular recognition by P-glycoprotein and cytochrome P450 3A4. Chem Res Toxicol. 2001 Dec;14(12):1596-603. Pubmed

              Comments
              Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:11