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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
Thioplex
External Identifiers Not Available
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Thio Tepa Inj 15mg/vialpowder for solution15 mgoral; rectal; surgical; vaginalLederle Cyanamid Canada Inc.1959-12-311997-11-24Canada
Thiotepa - (pws 15 Mg/vial)powder for solution15 mgintracavitary; intravesicular; intravenousWyeth Canada1997-08-252004-09-15Canada
Approved Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Thiotepainjection, powder, lyophilized, for solution15 mg/1.5mLintracavitary; intravenous; intravesicalWest Ward Pharmaceuticals Corp2001-06-01Not applicableUs
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixturesNot Available
SaltsNot Available
Categories
UNII905Z5W3GKH
CAS number52-24-4
WeightAverage: 189.218
Monoisotopic: 189.048954601
Chemical FormulaC6H12N3PS
InChI KeyInChIKey=FOCVUCIESVLUNU-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)-λ⁵-phosphanethione
SMILES
S=P(N1CC1)(N1CC1)N1CC1
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as organic thiophosphoric acids and derivatives. These are organic compounds containing the thiophosphoric acid functional group or a derivative thereof, with the general structure RP(R')(R'')=S, where R,R',R'' = O,N, halogen residue.
KingdomOrganic compounds
Super ClassOrganophosphorus compounds
ClassOrganothiophosphorus compounds
Sub ClassOrganic thiophosphoric acids and derivatives
Direct ParentOrganic thiophosphoric acids and derivatives
Alternative Parents
Substituents
  • Organic thiophosphoric acid or derivatives
  • Azacycle
  • Organoheterocyclic compound
  • Aziridine
  • Hydrocarbon derivative
  • Organonitrogen compound
  • Aliphatic heteromonocyclic compound
Molecular FrameworkAliphatic heteromonocyclic compounds
External DescriptorsNot Available
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.
Related Articles
AbsorptionNot Available
Volume of distributionNot Available
Protein bindingNot Available
MetabolismNot Available
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
PropertyValueProbability
Human Intestinal Absorption+0.8788
Blood Brain Barrier+0.9823
Caco-2 permeable-0.5097
P-glycoprotein substrateNon-substrate0.7362
P-glycoprotein inhibitor INon-inhibitor0.8096
P-glycoprotein inhibitor IINon-inhibitor0.9946
Renal organic cation transporterNon-inhibitor0.7874
CYP450 2C9 substrateNon-substrate0.7897
CYP450 2D6 substrateNon-substrate0.9116
CYP450 3A4 substrateNon-substrate0.7558
CYP450 1A2 substrateNon-inhibitor0.6474
CYP450 2C9 inhibitorNon-inhibitor0.7225
CYP450 2D6 inhibitorNon-inhibitor0.8794
CYP450 2C19 inhibitorNon-inhibitor0.593
CYP450 3A4 inhibitorNon-inhibitor0.8618
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.7358
Ames testAMES toxic0.9107
CarcinogenicityNon-carcinogens0.8992
BiodegradationNot ready biodegradable0.8949
Rat acute toxicity3.8842 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.7707
hERG inhibition (predictor II)Non-inhibitor0.866
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
Packagers
Dosage forms
FormRouteStrength
Powder for solutionoral; rectal; surgical; vaginal15 mg
Injection, powder, lyophilized, for solutionintracavitary; intravenous; intravesical15 mg/1.5mL
Powder for solutionintracavitary; intravesicular; intravenous15 mg
Prices
Unit descriptionCostUnit
Thiotepa 30 mg vial285.0USD vial
Thiotepa 15 mg vial69.6USD vial
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 Solubility9.27 mg/mLALOGPS
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
Polarizability18.23 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
Spectra
Spectrum TypeDescriptionSplash Key
MSMass Spectrum (Electron Ionization)splash10-00kn-6900000000-6d6b7c109663ea65ad79View in MoNA
References
Synthesis Reference

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

US4918199
General References
  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:10913381 ]
External Links
ATC CodesL01AC01
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSNot Available
Interactions
Drug Interactions
Drug
BupropionThe serum concentration of Bupropion can be increased when it is combined with Thiotepa.
ClozapineThe risk or severity of adverse effects can be increased when Thiotepa is combined with Clozapine.
DenosumabThe risk or severity of adverse effects can be increased when Denosumab is combined with Thiotepa.
LeflunomideThe risk or severity of adverse effects can be increased when Thiotepa is combined with Leflunomide.
MetamizoleThe risk or severity of adverse effects can be increased when Metamizole is combined with Thiotepa.
MethadoneThe metabolism of Methadone can be decreased when combined with Thiotepa.
NatalizumabThe risk or severity of adverse effects can be increased when Thiotepa is combined with Natalizumab.
PimecrolimusThe risk or severity of adverse effects can be increased when Pimecrolimus is combined with Thiotepa.
RoflumilastRoflumilast may increase the immunosuppressive activities of Thiotepa.
Sipuleucel-TThe therapeutic efficacy of Sipuleucel-T can be decreased when used in combination with Thiotepa.
TacrolimusThe risk or severity of adverse effects can be increased when Tacrolimus is combined with Thiotepa.
TofacitinibThiotepa may increase the immunosuppressive activities of Tofacitinib.
TrastuzumabTrastuzumab may increase the neutropenic activities of Thiotepa.
Food InteractionsNot Available

Targets

1. DNA
Kind
Nucleotide
Organism
Human
Pharmacological action
yes
Actions
cross-linking/alkylation
General Function:
Used for biological information storage.
Specific Function:
DNA contains the instructions needed for an organism to develop, survive and reproduce.
Molecular Weight:
2.15 x 1012 Da
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. doi: 10.1186/bcr2570. Epub 2010 May 10. [PubMed:20459744 ]
  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:20454509 ]
  3. Lestuzzi C: Neoplastic pericardial disease: Old and current strategies for diagnosis and management. World J Cardiol. 2010 Sep 26;2(9):270-9. doi: 10.4330/wjc.v2.i9.270. [PubMed:21160603 ]
  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:10913381 ]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
Steroid hydroxylase activity
Specific Function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Acts as a 1,4-cineole 2-exo-monooxygenase.
Gene Name:
CYP2B6
Uniprot ID:
P20813
Molecular Weight:
56277.81 Da
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. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]
  2. Drug Interactions: Cytochrome P450 Drug Interaction Table [Link]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Vitamin d3 25-hydroxylase activity
Specific Function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiot...
Gene Name:
CYP3A4
Uniprot ID:
P08684
Molecular Weight:
57342.67 Da
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. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]
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Drug created on September 07, 2007 14:54 / Updated on September 16, 2013 17:25