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Identification
NameThiotepa
Accession NumberDB04572
TypeSmall Molecule
GroupsApproved
Description

N,N’N’-triethylenethiophosphoramide (ThioTEPA) is a cancer chemotherapeutic member of the alkylating agent group, now in use for over 50 years. It is a stable derivative of N,N’,N’’- triethylenephosphoramide (TEPA). It is mostly used to treat breast cancer, ovarian cancer and bladder cancer. It is also used as conditioning for Bone marrow transplantation. Its main toxicity is myelosuppression.

Structure
Thumb
Synonyms
SynonymLanguageCode
ThioplexNot AvailableNot Available
SaltsNot Available
Brand namesNot Available
Brand mixturesNot Available
CategoriesNot Available
CAS number52-24-4
WeightAverage: 189.218
Monoisotopic: 189.048954601
Chemical FormulaC6H12N3PS
InChI KeyFOCVUCIESVLUNU-UHFFFAOYSA-N
InChI
InChI=1S/C6H12N3PS/c11-10(7-1-2-7,8-3-4-8)9-5-6-9/h1-6H2
IUPAC Name
tris(aziridin-1-yl)-$l^{5}-phosphanethione
SMILES
S=P(N1CC1)(N1CC1)N1CC1
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassAziridines
SubclassNot Available
Direct parentAziridines
Alternative parentsPolyamines
Substituentsorganonitrogen compound
Classification descriptionThis compound belongs to the aziridines. These are organic compounds containing a saturated three-member heterocycle with one amino group and two methylene groups.
Pharmacology
IndicationThioTEPA is used a as conditioning treatment prior to allogeneic or autologous haematopoietic progenitor cell transplantation (HPCT) in haematological diseases in adult and paediatric patients. Also, when high dose chemotherapy with HPCT support it is appropriate for the treatment of solid tumours in adult and paediatric patients.
PharmacodynamicsThe unstable nitrogen-carbon groups alkylate with DNA causing irrepairable DNA damage. They stop tumor growth by crosslinking guanine nucleobases 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. These drugs act nonspecifically.
Mechanism of actionThe alkyl group is attached to the guanine base of DNA, at the number 7 nitrogen atom of the imidazole ring. They stop tumor growth by crosslinking guanine nucleobases 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. These drugs act nonspecifically.
AbsorptionNot Available
Volume of distributionNot Available
Protein bindingNot Available
Metabolism
Route of eliminationUrinary excretion of 14C-labeled thiotepa and metabolites in a 34-year old patient with metastatic carcinoma of the cecum who received a dose of 0.3 mg/kg intravenously was 63%.
Half life1.5 to 4.1 hours
Clearance
  • 446 +/- 63 mL/min [female patients (45 to 84 years) with advanced stage ovarian cancer receiving 60 mg and 80 mg thiotepa by intravenous infusion on subsequent courses given at 4-week intervals]
ToxicityNot Available
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.8788
Blood Brain Barrier + 0.9823
Caco-2 permeable - 0.5097
P-glycoprotein substrate Non-substrate 0.7362
P-glycoprotein inhibitor I Non-inhibitor 0.8096
P-glycoprotein inhibitor II Non-inhibitor 0.9946
Renal organic cation transporter Non-inhibitor 0.7874
CYP450 2C9 substrate Non-substrate 0.7897
CYP450 2D6 substrate Non-substrate 0.9116
CYP450 3A4 substrate Non-substrate 0.7558
CYP450 1A2 substrate Non-inhibitor 0.6474
CYP450 2C9 substrate Non-inhibitor 0.7225
CYP450 2D6 substrate Non-inhibitor 0.8794
CYP450 2C19 substrate Non-inhibitor 0.593
CYP450 3A4 substrate Non-inhibitor 0.8618
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.7358
Ames test AMES toxic 0.9107
Carcinogenicity Non-carcinogens 0.8992
Biodegradation Not ready biodegradable 0.8949
Rat acute toxicity 3.8842 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.7707
hERG inhibition (predictor II) Non-inhibitor 0.866
Pharmacoeconomics
Manufacturers
  • Immunex corp
  • App pharmaceuticals llc
  • Bedford laboratories div ben venue laboratories inc
  • Teva parenteral medicines inc
Packagers
Dosage formsNot Available
Prices
Unit descriptionCostUnit
Thiotepa 30 mg vial285.0USDvial
Thiotepa 15 mg vial69.6USDvial
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point51.5 °CPhysProp
water solubility1.9E+005 mg/L (at 25 °C)MERCK INDEX (1996)
logP0.53HANSCH,C ET AL. (1995)
Predicted Properties
PropertyValueSource
Water Solubility9.27ALOGPS
logP0.17ALOGPS
logP-1ChemAxon
logS-1.3ALOGPS
pKa (Strongest Basic)-0.3ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area9.03 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity50.72 m3·mol-1ChemAxon
Polarizability18.3 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Spectra
Spectra
References
Synthesis Reference

John Kazan, “Process for producing thiotepa.” U.S. Patent US4918199, issued February, 1954.

US4918199
General Reference
  1. Maanen MJ, Smeets CJ, Beijnen JH: Chemistry, pharmacology and pharmacokinetics of N,N’,N" -triethylenethiophosphoramide (ThioTEPA). Cancer Treat Rev. 2000 Aug;26(4):257-68. Pubmed
  2. Maanen MJ, Smeets CJ, Beijnen JH: Chemistry, pharmacology and pharmacokinetics of N,N’,N" -triethylenethiophosphoramide (ThioTEPA). Cancer Treat Rev. 2000 Aug;26(4):257-68. Pubmed
External Links
ResourceLink
KEGG DrugD00583
KEGG CompoundC07641
PharmGKBPA451668
RxListhttp://www.rxlist.com/thiotepa-drug.htm
Drugs.comhttp://www.drugs.com/cdi/thiotepa.html
WikipediaThiotepa
ATC CodesL01AC01
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSNot Available
Interactions
Drug Interactions
Drug
BendamustineIncreases toxicity through pharmacodynamic synergism. Additive myelosuppression.
BupropionThiotepa, a strong CYP2B6 inhibitor, may decrease the metabolism and clearance of Bupropion, a CYP2B6 substrate. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Bupropion if Thiotepa is initiated, discontinued or dose changed.
CyclophosphamideThiotepa, 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.
FosphenytoinPossible increase in thiotepa levels
IrinotecanThiotepa, a strong CYP2B6 inhibitor, may decrease the metabolism and clearance of Irinotecan, a CYP2B6 substrate. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Irinotecan if Thiotepa is initiated, discontinued or dose changed.
KetamineThiotepa, a strong CYP2B6 inhibitor, may decrease the metabolism and clearance of Ketamine, a CYP2B6 substrate. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Ketamine if Thiotepa is initiated, discontinued or dose changed.
NatalizumabThe immunosuppressant, Thiotepa, may increase the adverse effects of Natalizumab. Increased risk of Progressive Multifocal Leukoencephalopathy (PML) and other infections. Concurrent therapy should be avoided.
PhenytoinPossible increase in thiotepa levels
PromethazineThiotepa, a strong CYP2B6 inhibitor, may decrease the metabolism and clearance of Promethazine, a CYP2B6 substrate. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Promethazine if Thiotepa is initiated, discontinued or dose changed.
SelegilineThiotepa, a strong CYP2B6 inhibitor, may decrease the metabolism and clearance of Selegiline, a CYP2B6 substrate. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Selegiline 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.
Food InteractionsNot Available

Targets

1. DNA

Kind: nucleotide

Organism: Human

Pharmacological action: yes

Actions: cross-linking/alkylation

Components

Name UniProt ID Details

References:

  1. Gor PP, Su HI, Gray RJ, Gimotty PA, Horn M, Aplenc R, Vaughan WP, Tallman MS, Rebbeck TR, DeMichele A: Cyclophosphamide-metabolizing enzyme polymorphisms and survival outcomes after adjuvant chemotherapy for node-positive breast cancer: a retrospective cohort study. Breast Cancer Res. 2010;12(3):R26. Epub 2010 May 10. Pubmed
  2. Lee PC, Kakadiya R, Su TL, Lee TC: Combination of bifunctional alkylating agent and arsenic trioxide synergistically suppresses the growth of drug-resistant tumor cells. Neoplasia. 2010 May;12(5):376-87. Pubmed
  3. Lestuzzi C: Neoplastic pericardial disease: Old and current strategies for diagnosis and management. World J Cardiol. 2010 Sep 26;2(9):270-9. Pubmed
  4. Maanen MJ, Smeets CJ, Beijnen JH: Chemistry, pharmacology and pharmacokinetics of N,N’,N" -triethylenethiophosphoramide (ThioTEPA). Cancer Treat Rev. 2000 Aug;26(4):257-68. Pubmed

Enzymes

1. Cytochrome P450 2B6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2B6 P20813 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

2. Cytochrome P450 3A4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 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

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Drug created on September 07, 2007 14:54 / Updated on September 16, 2013 17:25