Identification

Name
Thiotepa
Accession Number
DB04572
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.

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
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.

Associated Conditions
Contraindications & Blackbox Warnings
Learn about our commercial Contraindications & Blackbox Warnings data.
Learn More
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.

TargetActionsOrganism
ADNA
cross-linking/alkylation
Humans
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
Learn about our commercial Adverse Effects data.
Learn More
Toxicity
Not Available
Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
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.
DrugInteraction
AbametapirThe serum concentration of Thiotepa can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Thiotepa can be increased when combined with Abatacept.
AbciximabThe risk or severity of bleeding can be increased when Abciximab is combined with Thiotepa.
AcalabrutinibThe metabolism of Thiotepa can be decreased when combined with Acalabrutinib.
AcebutololThiotepa may increase the bradycardic activities of Acebutolol.
AcenocoumarolThe risk or severity of bleeding can be increased when Acenocoumarol is combined with Thiotepa.
AcetaminophenThe metabolism of Thiotepa can be increased when combined with Acetaminophen.
AcetazolamideThe metabolism of Thiotepa can be decreased when combined with Acetazolamide.
AcetylcholineThe risk or severity of adverse effects can be increased when Thiotepa is combined with Acetylcholine.
Acetylsalicylic acidThe risk or severity of bleeding can be increased when Acetylsalicylic acid is combined with Thiotepa.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

    Learn more
  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

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  • Action
    Action

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

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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

International/Other Brands
Thioplex
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
TepadinaInjection, powder, for solution15 mg/1Intracavitary; Intravenous; IntravesicalAmneal Pharmaceuticals LLC2017-08-15Not applicableUS flag
TepadinaInjection, powder, for solution15 mg/1Intracavitary; Intravenous; IntravesicalADIENNE SA2017-01-262018-08-01US flag
TepadinaPowder, for solution100 mgIntravenousADIENNE SA2017-10-31Not applicableCanada flag
TepadinaInjection, powder, for solution100 mg/1Intracavitary; Intravenous; IntravesicalAmneal Pharmaceuticals LLC2017-08-15Not applicableUS flag
TepadinaPowder, for solution15 mgIntravenousADIENNE SA2017-11-06Not applicableCanada flag
TepadinaInjection, powder, for solution100 mg/1Intracavitary; Intravenous; IntravesicalADIENNE SA2017-01-262018-08-01US flag
Thio Tepa Inj 15mg/vialPowder, for solutionOral; Rectal; VaginalLederle Cyanamid Canada Inc.1959-12-311997-11-24Canada flag
Thiotepa - (pws 15 Mg/vial)Powder, for solutionIntracavitary; Intravenous; IntravesicalWyeth Ltd.1997-08-252004-09-15Canada flag
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

    Learn more
  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
ThiotepaInjection, powder, lyophilized, for solution15 mg/1.5mLIntracavitary; Intravenous; IntravesicalBedford Pharmaceuticals2001-06-012012-09-30US flag
ThiotepaInjection, powder, for solution15 mg/1Intracavitary; Intravenous; IntravesicalMsn Laboratories Private Limited2020-03-04Not applicableUS flag
ThiotepaInjection, powder, lyophilized, for solution15 mg/1Intracavitary; Intravenous; IntravesicalDr.Reddy's Laboratories Inc.,2018-05-04Not applicableUS flag
ThiotepaInjection, powder, lyophilized, for solution15 mg/1Intracavitary; Intravenous; IntravesicalNovadoz Pharmaceuticals Llc2020-02-01Not applicableUS flag
ThiotepaInjection, powder, lyophilized, for solution15 mg/1.5mLIntracavitary; Intravenous; IntravesicalHikma Pharmaceuticals USA Inc.2001-06-01Not applicableUS flag
ThiotepaInjection, powder, lyophilized, for solution15 mg/15mgIntracavitary; Intravenous; IntravesicalSTI Pharma LLC2016-10-07Not applicableUS flag
ThiotepaInjection, powder, lyophilized, for solution15 mg/1.5mLIntracavitary; Intravenous; IntravesicalSagent Pharmaceuticals2018-06-15Not applicableUS flag
ThiotepaInjection, powder, for solution100 mg/1Intracavitary; Intravenous; IntravesicalMsn Laboratories Private Limited2020-03-04Not applicableUS flag
ThiotepaInjection, powder, lyophilized, for solution15 mg/1.5mLIntracavitary; Intravenous; IntravesicalHikma Pharmaceuticals USA Inc.2001-06-01Not applicableUS flag
ThiotepaInjection, powder, lyophilized, for solution100 mg/1Intracavitary; Intravenous; IntravesicalNovadoz Pharmaceuticals Llc2020-02-01Not applicableUS flag
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

    Learn more
  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

    Learn more

Categories

ATC Codes
L01AC01 — Thiotepa
Drug Categories
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)

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)-λ⁵-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
  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]
Human Metabolome Database
HMDB0015576
KEGG Drug
D00583
KEGG Compound
C07641
PubChem Compound
5453
PubChem Substance
46505958
ChemSpider
5254
BindingDB
50418086
RxNav
10473
ChEBI
9570
ChEMBL
CHEMBL671
ZINC
ZINC000001530867
PharmGKB
PA451668
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Thiotepa
AHFS Codes
  • 10:00.00 — Antineoplastic Agents

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedTreatmentAnemia / Graft Versus Host Disease (GVHD) / Leukemias / Malignant Lymphomas / Multiple Myeloma and Plasma Cell Neoplasm / Myelodysplastic Syndromes (MDS)1
4RecruitingTreatmentCentral Nervous System Embryonal Tumors / Medulloblastomas1
3Active Not RecruitingTreatmentChildhood Atypical Teratoid/Rhabdoid Tumor1
3Active Not RecruitingTreatmentExtraocular Retinoblastoma1
3Active Not RecruitingTreatmentLocalized Resectable Neuroblastoma / Localized Unresectable Neuroblastoma / Recurrent Neuroblastoma / Regional Neuroblastoma / Stage 4 Neuroblastoma / Stage 4S Neuroblastoma1
3Active Not RecruitingTreatmentUntreated Childhood Medulloblastoma / Untreated Childhood Supratentorial Primitive Neuroectodermal Tumor1
3CompletedTreatmentB-cell Childhood Acute Lymphoblastic Leukemia / Childhood Acute Lymphoblastic Leukemia in Remission / Graft Versus Host Disease (GVHD) / L1 Childhood Acute Lymphoblastic Leukemia / L2 Childhood Acute Lymphoblastic Leukemia / T-cell Childhood Acute Lymphoblastic Leukemia1
3CompletedTreatmentBreast Cancer5
3CompletedTreatmentLeukemias1
3CompletedTreatmentNeoplasms, Brain / Tumors of the Central Nervous System1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • APP Pharmaceuticals
  • Bedford Labs
  • Ben Venue Laboratories Inc.
  • Sicor Pharmaceuticals
Dosage Forms
FormRouteStrength
Injection, powder, for solutionIntravenous; Parenteral100 MG
Injection, powder, for solutionIntravenous; Parenteral15 MG
Powder, for solutionIntravenous100 mg
Powder, for solutionIntravenous15 mg
Powder, for solutionOral; Rectal; Vaginal
Injection, powder, for solutionIntracavitary; Intravenous; Intravesical100 mg/1
Injection, powder, for solutionIntracavitary; Intravenous; Intravesical15 mg/1
Injection, powder, lyophilized, for solutionIntracavitary; Intravenous; Intravesical100 mg/1
Injection, powder, lyophilized, for solutionIntracavitary; Intravenous; Intravesical15 mg/1.5mL
Injection, powder, lyophilized, for solutionIntracavitary; Intravenous; Intravesical15 mg/15mg
Injection, powder, lyophilized, for solutionIntracavitary; Intravenous; Intravesical15 mg/1
Powder, for solutionIntracavitary; Intravenous; Intravesical
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.
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)51.5 °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 FilterNoChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
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)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Mass Spectrum (Electron Ionization)MSsplash10-00kn-6900000000-6d6b7c109663ea65ad79
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0udj-2910000000-ba7d9f76d09c90907cd5

Targets

Kind
Nucleotide
Organism
Humans
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.
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

Details
1. Cytochrome P450 2B6
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
  1. Rae JM, Soukhova NV, Flockhart DA, Desta Z: Triethylenethiophosphoramide is a specific inhibitor of cytochrome P450 2B6: implications for cyclophosphamide metabolism. Drug Metab Dispos. 2002 May;30(5):525-30. doi: 10.1124/dmd.30.5.525. [PubMed:11950782]
  2. Flockhart Table of Drug Interactions [Link]
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
  1. 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. [PubMed:12107550]
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

Drug created on September 07, 2007 14:54 / Updated on October 21, 2020 01:55

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