Identification
- Summary
Thiotepa is an alkylating agent used to prevent graft rejection in stem cell transplantation and to treat a variety of malignancies including certain types of adenocarcinoma and superficial bladder carcinomas.
- Brand Names
- Tepadina
- Generic Name
- Thiotepa
- DrugBank Accession Number
- DB04572
- Background
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.
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Thiotepa (DB04572)
- Weight
- Average: 189.218
Monoisotopic: 189.048954601 - Chemical Formula
- C6H12N3PS
- Synonyms
- Thiotepa
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.
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Symptomatic treatment of Breast adenocarcinoma •••••••••••• Management of Effusion •••••••••••• Symptomatic treatment of Ovary adenocarcinoma •••••••••••• Treatment of Superficial papillary bladder cancer •••••••••••• - Contraindications & Blackbox Warnings
Prevent Adverse Drug Events TodayTap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events with our Clinical API- 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.
Target Actions Organism ADNA cross-linking/alkylationHumans - 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]
- Adverse Effects
Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!Improve decision support & research outcomes with our structured adverse effects data.- Toxicity
Not Available
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
- Not Available
Interactions
- Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwareAbametapir The serum concentration of Thiotepa can be increased when it is combined with Abametapir. Abatacept The metabolism of Thiotepa can be increased when combined with Abatacept. Abciximab The risk or severity of bleeding can be increased when Abciximab is combined with Thiotepa. Acalabrutinib The metabolism of Thiotepa can be decreased when combined with Acalabrutinib. Acebutolol Thiotepa may increase the bradycardic activities of Acebutolol. - Food Interactions
- Exercise caution with grapefruit products. Grapefruit inhibits the CYP3A4 metabolism of thiotepa, which may increase its serum concentration.
- Exercise caution with St. John's Wort. This herb induces CYP3A4 metabolism and may reduce serum levels of thiotepa.
Products
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- Thioplex
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Tepadina Injection, powder, for solution 100 mg/1 Intracavitary; Intravenous; Intravesical ADIENNE SA 2017-01-26 2018-08-01 US 
Tepadina Powder, for solution 15 mg / vial Intravenous ADIENNE SA 2017-11-06 Not applicable Canada 
Tepadina Injection, powder, for solution 15 mg/1 Intracavitary; Intravenous; Intravesical Amneal Pharmaceuticals LLC 2017-08-15 Not applicable US Tepadina Injection, powder, for solution 100 mg Intravenous Adienne S.R.L. S.U. 2022-05-04 Not applicable EU 
Tepadina Powder, for solution 400 mg / bag Intravenous ADIENNE SA Not applicable Not applicable Canada - Generic Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Thiotepa Injection, powder, for solution 100 mg/1 Intracavitary; Intravenous; Intravesical Meitheal Pharmaceuticals Inc 2023-12-26 Not applicable US Thiotepa Injection, powder, lyophilized, for solution 100 mg/1 Intracavitary; Intravenous; Intravesical Fresenius Kabi USA, LLC 2022-04-11 Not applicable US Thiotepa Injection, powder, lyophilized, for solution 15 mg/15mg Intracavitary; Intravenous; Intravesical STI Pharma LLC 2016-10-07 Not applicable US Thiotepa Injection, powder, lyophilized, for solution 15 mg/1.5mL Intracavitary; Intravenous; Intravesical Hikma Pharmaceuticals USA Inc. 2001-06-01 Not applicable US Thiotepa Injection, powder, for solution 100 mg/1 Intracavitary; Intravenous; Intravesical Msn Laboratories Private Limited 2020-03-04 Not applicable US
Categories
- ATC Codes
- L01AC01 — Thiotepa
- Drug Categories
- Alkylating Activity
- Alkylating Drugs
- Antineoplastic Agents
- Antineoplastic Agents, Alkylating
- Antineoplastic and Immunomodulating Agents
- Aziridines
- Azirines
- Cholinesterase Inhibitors
- Cytochrome P-450 CYP2B6 Inhibitors
- Cytochrome P-450 CYP2B6 Inhibitors (moderate)
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 CYP3A4 Substrates with a Narrow Therapeutic Index
- Cytochrome P-450 Enzyme Inhibitors
- Cytochrome P-450 Substrates
- Ethylene Imines
- Immunologic Factors
- Immunosuppressive Agents
- Myeloablative Agonists
- Myelosuppressive Agents
- Narrow Therapeutic Index Drugs
- Noxae
- Organophosphorus Compounds
- Phosphoramides
- Toxic Actions
- Triethylenephosphoramide
- Chemical TaxonomyProvided by Classyfire
- Description
- This 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.
- Kingdom
- Organic compounds
- Super Class
- Organic acids and derivatives
- Class
- Organic thiophosphoric acids and derivatives
- Sub Class
- Not Available
- Direct Parent
- Organic thiophosphoric acids and derivatives
- Alternative Parents
- Aziridines / Azacyclic compounds / Organopnictogen compounds / Organonitrogen compounds / Hydrocarbon derivatives
- Substituents
- Aliphatic heteromonocyclic compound / Azacycle / Aziridine / Hydrocarbon derivative / Organic nitrogen compound / Organic thiophosphoric acid or derivatives / Organoheterocyclic compound / Organonitrogen compound / Organopnictogen compound
- Molecular Framework
- Aliphatic heteromonocyclic compounds
- External Descriptors
- aziridines (CHEBI:9570)
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- 905Z5W3GKH
- CAS number
- 52-24-4
- InChI Key
- 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)-lambda5-phosphanethione
- SMILES
- S=P(N1CC1)(N1CC1)N1CC1
References
- Synthesis Reference
John Kazan, "Process for producing thiotepa." U.S. Patent US4918199, issued February, 1954.
US4918199- General References
- 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. [Article]
- External Links
- Human Metabolome Database
- HMDB0015576
- KEGG Drug
- D00583
- KEGG Compound
- C07641
- PubChem Compound
- 5453
- PubChem Substance
- 46505958
- ChemSpider
- 5254
- BindingDB
- 50418086
- 10473
- ChEBI
- 9570
- ChEMBL
- CHEMBL671
- ZINC
- ZINC000001530867
- PharmGKB
- PA451668
- RxList
- RxList Drug Page
- Drugs.com
- Drugs.com Drug Page
- Wikipedia
- Thiotepa
Clinical Trials
- Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
Phase Status Purpose Conditions Count 4 Active Not Recruiting Treatment Central Nervous System Embryonal Tumors / Medulloblastomas 1 4 Completed Treatment Anemia / Graft-versus-host Disease (GVHD) / Leukemias / Lymphoma / Multiple Myeloma and Plasma Cell Neoplasm / Myelodysplastic Syndrome 1 3 Active Not Recruiting Treatment Anaplastic Medulloblastoma / Medulloblastomas / Supratentorial Embryonal Tumor, Not Otherwise Specified / Untreated Childhood Supratentorial Primitive Neuroectodermal Tumor 1 3 Active Not Recruiting Treatment Breast Cancer 1 3 Active Not Recruiting Treatment Childhood Atypical Teratoid/Rhabdoid Tumor 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- APP Pharmaceuticals
- Bedford Labs
- Ben Venue Laboratories Inc.
- Sicor Pharmaceuticals
- Dosage Forms
Form Route Strength Injection, powder, for solution Intravenous 400 mg Injection, powder, for solution Intravenous; Parenteral 100 MG Injection, powder, for solution Intravenous; Parenteral 15 MG Powder, for solution Intravenous 100 mg / vial Powder, for solution Intravenous 15 mg / vial Powder, for solution Intravenous 400 MG Powder, for solution Intravenous 400 mg / bag Injection, solution, concentrate Intravenous 100 mg Injection, powder, lyophilized, for solution Intravenous 15 mg Powder, for solution Oral; Rectal; Vaginal 15 mg / vial Injection, powder, for solution Injection, powder, for solution Intracavitary; Intravenous; Intravesical 100 mg/1 Injection, powder, for solution Intracavitary; Intravenous; Intravesical 15 mg/1 Injection, powder, lyophilized, for solution Intracavitary; Intravenous; Intravesical 100 mg/1 Injection, powder, lyophilized, for solution Intracavitary; Intravenous; Intravesical 15 mg/1 Injection, powder, lyophilized, for solution Intracavitary; Intravenous; Intravesical 15 mg/15mg Injection, powder, lyophilized, for solution Intracavitary; Intravenous; Intravesical 15 mg/1.5mL Powder, for solution Intracavitary; Intravenous; Intravesical 15 mg / vial Injection, powder, for solution Parenteral 100 mg Injection, powder, for solution Parenteral 15 mg Injection, powder, for solution 100 MG Injection, powder, for solution 15 MG Injection, powder, for solution Intravenous 100 MG Injection, powder, for solution Intravenous 15 MG - Prices
Unit description Cost Unit Thiotepa 30 mg vial 285.0USD vial Thiotepa 15 mg vial 69.6USD 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 (°C) 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 9.27 mg/mL 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 Å2 Chemaxon Rotatable Bond Count 3 Chemaxon Refractivity 50.72 m3·mol-1 Chemaxon Polarizability 18.22 Å3 Chemaxon Number of Rings 3 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter No Chemaxon Veber's Rule Yes Chemaxon MDDR-like Rule No Chemaxon - 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 inhibitor Non-inhibitor 0.7225 CYP450 2D6 inhibitor Non-inhibitor 0.8794 CYP450 2C19 inhibitor Non-inhibitor 0.593 CYP450 3A4 inhibitor 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
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 138.8506658 predictedDarkChem Lite v0.1.0 [M-H]- 139.1360658 predictedDarkChem Lite v0.1.0 [M-H]- 138.9203658 predictedDarkChem Lite v0.1.0 [M-H]- 131.26314 predictedDeepCCS 1.0 (2019) [M+H]+ 138.9196658 predictedDarkChem Lite v0.1.0 [M+H]+ 138.9869658 predictedDarkChem Lite v0.1.0 [M+H]+ 138.9736658 predictedDarkChem Lite v0.1.0 [M+H]+ 133.809 predictedDeepCCS 1.0 (2019) [M+Na]+ 139.1245658 predictedDarkChem Lite v0.1.0 [M+Na]+ 139.2438658 predictedDarkChem Lite v0.1.0 [M+Na]+ 139.0077658 predictedDarkChem Lite v0.1.0 [M+Na]+ 141.90492 predictedDeepCCS 1.0 (2019)
Targets
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Yes
Cross-linking/alkylation
References
- 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. [Article]
- 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. [Article]
- 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. [Article]
- 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. [Article]
Enzymes
- Kind
- Protein
- Organism
- Humans
- 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 react...
- Gene Name
- CYP3A4
- Uniprot ID
- P08684
- Uniprot Name
- Cytochrome P450 3A4
- Molecular Weight
- 57342.67 Da
References
- Jacobson PA, Green K, Birnbaum A, Remmel RP: Cytochrome P450 isozymes 3A4 and 2B6 are involved in the in vitro human metabolism of thiotepa to TEPA. Cancer Chemother Pharmacol. 2002 Jun;49(6):461-7. doi: 10.1007/s00280-002-0453-3. Epub 2002 Apr 23. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- General Function
- Identical protein binding
- Specific Function
- Esterase with broad substrate specificity. Contributes to the inactivation of the neurotransmitter acetylcholine. Can degrade neurotoxic organophosphate esters.
- Gene Name
- BCHE
- Uniprot ID
- P06276
- Uniprot Name
- Cholinesterase
- Molecular Weight
- 68417.575 Da
- Kind
- Protein
- Organism
- Humans
- 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 un...
- Gene Name
- CYP2B6
- Uniprot ID
- P20813
- Uniprot Name
- Cytochrome P450 2B6
- Molecular Weight
- 56277.81 Da
References
Drug created at September 07, 2007 20:54 / Updated at February 20, 2024 23:54