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Identification
Name Thiotepa
Accession Number DB04572
Type small molecule
Groups approved
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
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms Not Available
Salts Not Available
Brand names Not Available
Brand mixtures Not Available
Categories
  • Alkylating Agents
  • Antineoplastic Agents, Alkylating
CAS number 52-24-4
Weight Average: 189.218
Monoisotopic: 189.048954601
Chemical Formula C6H12N3PS
InChI Key InChIKey=FOCVUCIESVLUNU-UHFFFAOYSA-N
InChI
InChI=1S/C6H12N3PS/c11-10(7-1-2-7,8-3-4-8)9-5-6-9/h1-6H2
Plain Text
IUPAC Name
tris(aziridin-1-yl)-$l^{5}-phosphanethione
SMILES
S=P(N1CC1)(N1CC1)N1CC1
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Not Available
Classes Not Available
Substructures Not Available
Pharmacology
Indication ThioTEPA 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.
Pharmacodynamics The 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 action The 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.
Absorption Not Available
Volume of distribution Not Available
Protein binding Not Available
Metabolism Not Available
Route of elimination Urinary 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 life 1.5 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]
Toxicity Not Available
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Immunex corp
  • App pharmaceuticals llc
  • Bedford laboratories div ben venue laboratories inc
  • Teva parenteral medicines inc
Packagers
Dosage forms Not Available
Prices
Unit description Cost Unit
Thiotepa 30 mg vial 285.0 USD vial
Thiotepa 15 mg vial 69.6 USD vial
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents Not Available
Properties
State solid
Experimental Properties
Property Value Source
melting point 51.5 °C PhysProp
water solubility 1.9E+005 mg/L (at 25 °C) MERCK INDEX (1996)
logP 0.53 HANSCH,C ET AL. (1995)
Predicted Properties
Property Value Source
water solubility 9.27e+00 g/l ALOGPS
logP 0.17 ALOGPS
logP -1 ChemAxon
logS -1.3 ALOGPS
pKa (strongest basic) -0.3 ChemAxon
physiological charge 0 ChemAxon
hydrogen acceptor count 3 ChemAxon
hydrogen donor count 0 ChemAxon
polar surface area 9.03 ChemAxon
rotatable bond count 3 ChemAxon
refractivity 50.72 ChemAxon
polarizability 18.3 ChemAxon
References
Synthesis Reference Not Available
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
Resource Link
KEGG Drug D00583 Link_out
KEGG Compound C07641 Link_out
PharmGKB PA451668 Link_out
RxList http://www.rxlist.com/thiotepa-drug.htm Link_out
Drugs.com http://www.drugs.com/cdi/thiotepa.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Thiotepa Link_out
ATC Codes
  • L01AC01
AHFS Codes Not Available
PDB Entries Not Available
FDA label Not Available
MSDS Not Available
Interactions
Drug Interactions
Drug Interaction
Bendamustine Increases toxicity through pharmacodynamic synergism. Additive myelosuppression.
Bupropion Thiotepa, 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.
Cyclophosphamide Thiotepa, 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.
Fosphenytoin Possible increase in thiotepa levels
Irinotecan Thiotepa, 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.
Ketamine Thiotepa, 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.
Natalizumab The immunosuppressant, Thiotepa, may increase the adverse effects of Natalizumab. Increased risk of Progressive Multifocal Leukoencephalopathy (PML) and other infections. Concurrent therapy should be avoided.
Phenytoin Possible increase in thiotepa levels
Promethazine Thiotepa, 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.
Selegiline Thiotepa, 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.
Trastuzumab Trastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events.
Food Interactions Not Available
Targets

1. DNA

Pharmacological action: yes
Actions: cross-linking/alkylation

DNA is the molecule of heredity, as it is responsible for the genetic propagation of most inherited traits. It is a polynucleic acid that carries genetic information on cell growth, division, and function. DNA consists of two long strands of nucleotides twisted into a double helix and held together by hydrogen bonds. The sequence of nucleotides determines hereditary characteristics. Each strand serves as the template for subsequent DNA replication and as a template for mRNA production, leading to protein synthesis via ribosomes.

Gene Sequence: FASTA

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

Actions: inhibitor

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

UniProt ID: P20813 Link_out
Gene: CYP2B6 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: substrate

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 xenobiotics. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out
Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
Comments
Drug created on September 07, 2007 14:54 / Updated on February 08, 2013 16:23