Identification
- Summary
Triethylenetetramine is a copper chelating agent used for the management of Wilson's disease in cases where penicillamine therapy is clinically inappropriate.
- Brand Names
- Cuvrior, Syprine
- Generic Name
- Triethylenetetramine
- DrugBank Accession Number
- DB06824
- Background
Triethylenetatramine (TETA), also known as trientine, is a potent and selective copper (II)-selective chelator. It is a structural analog of linear polyamine compounds, spermidine and spermine. TETA was first developed in Germany in 1861 and its chelating properties were first recognized in 1925.4 Initially approved by the FDA in 1985 as a second-line treatment for Wilson's disease,5 TETA is currently indicated to treat adults with stable Wilson’s disease who are de-coppered and tolerant to penicillamine.8
TETA has been investigated in clinical trials for the treatment of heart failure in patients with diabetes.2,3,4,5,6
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Triethylenetetramine (DB06824)
- Weight
- Average: 146.2339
Monoisotopic: 146.153146596 - Chemical Formula
- C6H18N4
- Synonyms
- TETA
- Trien
- Trientine
- External IDs
- GC811007
Pharmacology
- Indication
Triethylenetetramine is a copper chelator indicated for the treatment of adult patients with stable Wilson’s disease who are de-coppered and tolerant to penicillamine.8
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Management of Wilson's disease •••••••••••• ••••• •••••• •••••• ••••••• ••••••••• •• ••••••••••••• •••••• - Contraindications & Blackbox Warnings
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Triethylenetetramine (TETA) is a selective copper(II) chelator that works to promote urinary copper excretion.8 It was shown to reduce excess body copper storage and ameliorate symptoms of Wilson’s disease. In rats with diabetes mellitus, intravenous administration of TETA led to a dose-dependent increase in urinary copper excretion.1
In preliminary studies, TETA was shown to ameliorate left ventricular hypertrophy in both human and animal subjects with diabetes. In animal models, TETA was also shown to reverse manifestations of diabetic nephropathy, including nephromegaly, renal fibrosis, glomerulosclerosis, and albuminuria, without lowering hyperglycemia.2 This finding may be explained by TETA chelating copper cations, which are pro-oxidant and activate pathways that produce excessive reactive oxygen species (ROS) that cause tissue injury.6 TETA was shown to possess anti-angiogenesis properties, as copper is an essential element for angiogenesis in cancer cells. TETA was shown to inhibit telomerase, suggesting that it may exhibit an inhibitory effect or cytotoxicity on tumor growth. Based on these early findings, TETA has been studied for its anticancer effects.4
- Mechanism of action
Wilson's disease is an autosomal recessive genetic disorder that leads to copper accumulation in the tissues. It is characterized by an array of neurologic or psychiatric symptoms as well as liver disease.4,7 One of the treatments for Wilson's disease is the use of copper-chelating agents, such as triethylenetetramine (TETA). TETA forms a stable complex with copper(II), which is then is readily eliminated through urinary excretion. TETA also chelates copper in the intestinal tract, reducing intestinal copper absorption by 80%.4,8 TETA and its metabolite, N1-acetyltriethylenetetramine (MAT), are also capable of binding divalent iron, divalent zinc, magnesium, and manganese.4
- Absorption
TETA is poorly absorbed from the gastrointestinal tract with an oral bioavailability ranging from 6% to 18%.1 TETA has the potential to chelate non-copper cations in mineral supplements and other oral drugs, resulting in altered drug absorption; thus, TETA should be administered at least one hour apart from these medications.8
The median Tmax ranges from 1.25 to 2 hours. Mean Cmax (± SD) of triethylenetetramine (TETA) was 2030 ± 981 ng/mL following oral administration of 900 mg TETA and 3430 ± 1480 ng/mL following administration of 1500 mg TETA. The systemic exposure (AUC) of TETA increased in a dose-proportional manner over the range of 900 mg to 1500 mg TETA. The mean AUCinf (± SD) was 9750 ± 4910 ngxh/mL at 900 mg and 17200 ± 9470 ngxh/mL at 1500 mg.8
- Volume of distribution
TETA is widely distributed in tissues, with relatively high concentrations measured in liver, heart, and kidney. It is prone to accumulation in certain tissues.4 In healthy adult volunteers receiving oral capsules of TETA, the apparent volume of distribution of steady state was 645 L.1
- Protein binding
Not Available
- Metabolism
The majority of absorbed TETA is extensively metabolized into acetyl-metabolites.1 TETA undergoes acetylation mediated by diamine acetyltransferase, also known as spermidine/spermine N1-acetyltranferase,2,4 to form two major active metabolites, N1-acetyltriethylenetetramine (MAT) and N1,N10-diacetyltriethylenetetramine (DAT).8 The chelating activity of MAT is significantly lower than that of TETA.4
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- Route of elimination
TETA and its metabolites, MAT and DAT, are mainly excreted in the urine.8 Approximately less than 1% of the administered dose is renally excreted as unchanged drug within the first six hours of dosing. About 8% of the dose is excreted as two major metabolites of TETA, MAT and DAT. Urinary excretion of metabolites occurs later than the excretion of the unchanged parent drug: it continues for 26 hours or longer.1
- Half-life
The mean terminal half-life (t1/2) ranged from 13.8 to 16.5 hours.8
- Clearance
In healthy adult volunteers receiving oral capsules of TETA, the oral total clearance was 69.5 L/h.1
- Adverse Effects
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The oral LD50 was 2500 mg/kg in rats. The dermal LD50 was 550 mg/kg in rabbits.9
Occasional cases of trientine overdose have been reported. A large overdose of 60 g of trientine hydrochloride resulted in nausea, vomiting, dizziness, mild acute kidney injury, mild hypophosphatemia, low serum zinc, and low serum copper: the patient recovered following intravenous hydration and supportive measures. There is no antidote for an acute overdose from trientine. Chronic use of trientine at dosages above the maximum recommended dosage has resulted in sideroblastic anemia.8
- 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 softwareAbacavir Abacavir may decrease the excretion rate of Triethylenetetramine which could result in a higher serum level. Aceclofenac Aceclofenac may decrease the excretion rate of Triethylenetetramine which could result in a higher serum level. Acemetacin Acemetacin may decrease the excretion rate of Triethylenetetramine which could result in a higher serum level. Acetaminophen Acetaminophen may decrease the excretion rate of Triethylenetetramine which could result in a higher serum level. Acetazolamide The excretion of Triethylenetetramine can be increased when combined with Acetazolamide. - Food Interactions
- Avoid concomitant mineral supplements. Administer CUVRIOR at least 1 hour before or 2 hours after administration of other mineral supplements.
- Take at least 2 hours before or after iron supplements. Iron and triethylenetetramine inhibit each others absorption.
- Take on an empty stomach. Take CUVRIOR one hour before or two hours after eating a meal or at least one hour of separation from other drugs, milk, or food.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Product Ingredients
Ingredient UNII CAS InChI Key Trientine hydrochloride HC3NX54582 38260-01-4 WYHIICXRPHEJKI-UHFFFAOYSA-N Trientine tetrahydrochloride 7360URE56Q 4961-40-4 OKHMDSCYUWAQPT-UHFFFAOYSA-N - Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Cufence Capsule 200 mg Oral Univar Solutions Bv 2020-12-16 Not applicable EU 
Cuprior Tablet, film coated 150 mg Oral Gmp Orphan Sa 2020-12-16 Not applicable EU Cuprior Tablet, film coated 150 mg Oral Gmp Orphan Sa 2020-12-16 Not applicable EU Cuvrior Tablet, film coated 300 mg/1 Oral Orphalan SA 2022-09-14 Not applicable US 
Syprine Capsule 250 mg/1 Oral Aton Pharma, Inc. 1985-11-08 2016-08-26 US - Generic Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Mar-trientine Capsule 250 mg Oral Marcan Pharmaceuticals Inc 2020-11-10 Not applicable Canada 
Trientine Hydrochloride Capsule 250 mg/1 Oral Lannett Company Inc. 2020-12-22 Not applicable US Trientine Hydrochloride Capsule, gelatin coated 250 mg/1 Oral Amneal Pharmaceuticals NY LLC 2019-02-08 Not applicable US Trientine Hydrochloride Capsule 250 mg/1 Oral Navinta Llc 2020-12-05 Not applicable US Trientine Hydrochloride Capsule 500 mg/1 Oral Rising Pharma Holdings, Inc. 2023-09-22 Not applicable US
Categories
- ATC Codes
- A16AX12 — Trientine
- Drug Categories
- Alimentary Tract and Metabolism
- Amines
- Chelating Agents
- Compounds used in a research, industrial, or household setting
- Copper Chelator
- Diamines
- Drugs that are Mainly Renally Excreted
- Ethylenediamines
- Heavy Metal Antagonists
- Metal Chelating Activity
- Metal Chelator
- Polyamines
- Sequestering Agents
- Various Alimentary Tract and Metabolism Products
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as dialkylamines. These are organic compounds containing a dialkylamine group, characterized by two alkyl groups bonded to the amino nitrogen.
- Kingdom
- Organic compounds
- Super Class
- Organic nitrogen compounds
- Class
- Organonitrogen compounds
- Sub Class
- Amines
- Direct Parent
- Dialkylamines
- Alternative Parents
- Organopnictogen compounds / Monoalkylamines / Hydrocarbon derivatives
- Substituents
- Aliphatic acyclic compound / Hydrocarbon derivative / Organopnictogen compound / Primary aliphatic amine / Primary amine / Secondary aliphatic amine
- Molecular Framework
- Aliphatic acyclic compounds
- External Descriptors
- tetraamine, polyazaalkane (CHEBI:39501)
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- SJ76Y07H5F
- CAS number
- 112-24-3
- InChI Key
- VILCJCGEZXAXTO-UHFFFAOYSA-N
- InChI
- InChI=1S/C6H18N4/c7-1-3-9-5-6-10-4-2-8/h9-10H,1-8H2
- IUPAC Name
- (2-aminoethyl)({2-[(2-aminoethyl)amino]ethyl})amine
- SMILES
- NCCNCCNCCN
References
- General References
- Cho HY, Blum RA, Sunderland T, Cooper GJ, Jusko WJ: Pharmacokinetic and pharmacodynamic modeling of a copper-selective chelator (TETA) in healthy adults. J Clin Pharmacol. 2009 Aug;49(8):916-28. doi: 10.1177/0091270009337939. [Article]
- Lu J, Poppitt SD, Othman AA, Sunderland T, Ruggiero K, Willett MS, Diamond LE, Garcia WD, Roesch BG, Cooper GJ: Pharmacokinetics, pharmacodynamics, and metabolism of triethylenetetramine in healthy human participants: an open-label trial. J Clin Pharmacol. 2010 Jun;50(6):647-58. doi: 10.1177/0091270009349379. Epub 2010 Feb 9. [Article]
- Lu J, Chan YK, Gamble GD, Poppitt SD, Othman AA, Cooper GJ: Triethylenetetramine and metabolites: levels in relation to copper and zinc excretion in urine of healthy volunteers and type 2 diabetic patients. Drug Metab Dispos. 2007 Feb;35(2):221-7. Epub 2006 Nov 15. [Article]
- Lu J: Triethylenetetramine pharmacology and its clinical applications. Mol Cancer Ther. 2010 Sep;9(9):2458-67. doi: 10.1158/1535-7163.MCT-10-0523. Epub 2010 Jul 26. [Article]
- Cooper GJ: Therapeutic potential of copper chelation with triethylenetetramine in managing diabetes mellitus and Alzheimer's disease. Drugs. 2011 Jul 9;71(10):1281-320. doi: 10.2165/11591370-000000000-00000. [Article]
- Lu J, Gong D, Choong SY, Xu H, Chan YK, Chen X, Fitzpatrick S, Glyn-Jones S, Zhang S, Nakamura T, Ruggiero K, Obolonkin V, Poppitt SD, Phillips AR, Cooper GJ: Copper(II)-selective chelation improves function and antioxidant defences in cardiovascular tissues of rats as a model of diabetes: comparisons between triethylenetetramine and three less copper-selective transition-metal-targeted treatments. Diabetologia. 2010 Jun;53(6):1217-26. doi: 10.1007/s00125-010-1698-8. Epub 2010 Mar 11. [Article]
- Authors unspecified: EASL Clinical Practice Guidelines: Wilson's disease. J Hepatol. 2012 Mar;56(3):671-85. doi: 10.1016/j.jhep.2011.11.007. [Article]
- FDA Approved Drug Products: CUVRIOR (trientine tetrahydrochloride) tablets, for oral use [Link]
- CDH Chemicals: Triethylenetetramine MSDS [Link]
- External Links
- Human Metabolome Database
- HMDB0259196
- KEGG Compound
- C07166
- PubChem Compound
- 5565
- PubChem Substance
- 310264897
- ChemSpider
- 21106175
- BindingDB
- 50323751
- 10798
- ChEBI
- 39501
- ChEMBL
- CHEMBL609
- ZINC
- ZINC000019364225
- PDBe Ligand
- 104
- Wikipedia
- Triethylenetetramine
- PDB Entries
- 1dj6
- MSDS
- Download (48.7 KB)
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 Unknown Status Treatment Wilson's Disease 1 3 Completed Treatment Wilson's Disease 2 2 Active Not Recruiting Treatment Hypertrophic Cardiomyopathy (HCM) 1 2 Withdrawn Prevention Macular Edema Following Cataract Surgery 1 1 Completed Treatment Advanced Malignant Neoplasm 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Capsule Oral 167 mg Tablet Oral 150 MG Tablet, film coated Oral 150 MG Tablet, film coated Oral 300 mg/1 Capsule Oral 250 mg Capsule Oral 250 mg/1 Capsule Oral 200 mg Capsule Oral 500 mg/1 Capsule, gelatin coated Oral 250 mg/1 - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US11072577 No 2021-07-27 2039-05-03 US US10988436 No 2021-04-27 2039-05-03 US
Properties
- State
- Liquid
- Experimental Properties
Property Value Source melting point (°C) 12 https://www.cdhfinechemical.com/images/product/msds/37_1605852200_TriethyleneTetramine-CASNO-112-24-3-MSDS.pdf boiling point (°C) 266-267 https://www.cdhfinechemical.com/images/product/msds/37_1605852200_TriethyleneTetramine-CASNO-112-24-3-MSDS.pdf water solubility Soluble https://www.cdhfinechemical.com/images/product/msds/37_1605852200_TriethyleneTetramine-CASNO-112-24-3-MSDS.pdf - Predicted Properties
Property Value Source Water Solubility 27.5 mg/mL ALOGPS logP -1.8 ALOGPS logP -2.2 Chemaxon logS -0.73 ALOGPS pKa (Strongest Basic) 9.77 Chemaxon Physiological Charge 2 Chemaxon Hydrogen Acceptor Count 4 Chemaxon Hydrogen Donor Count 4 Chemaxon Polar Surface Area 76.1 Å2 Chemaxon Rotatable Bond Count 7 Chemaxon Refractivity 43.32 m3·mol-1 Chemaxon Polarizability 18.04 Å3 Chemaxon Number of Rings 0 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 128.66359 predictedDeepCCS 1.0 (2019) [M+H]+ 131.15263 predictedDeepCCS 1.0 (2019) [M+Na]+ 139.97066 predictedDeepCCS 1.0 (2019)
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Diamine n-acetyltransferase activity
- Specific Function
- Enzyme which catalyzes the acetylation of polyamines. Substrate specificity: norspermidine = spermidine >> spermine > N(1)-acetylspermine > putrescine. This highly regulated enzyme allows a fine at...
- Gene Name
- SAT1
- Uniprot ID
- P21673
- Uniprot Name
- Diamine acetyltransferase 1
- Molecular Weight
- 20023.8 Da
References
- Lu J, Poppitt SD, Othman AA, Sunderland T, Ruggiero K, Willett MS, Diamond LE, Garcia WD, Roesch BG, Cooper GJ: Pharmacokinetics, pharmacodynamics, and metabolism of triethylenetetramine in healthy human participants: an open-label trial. J Clin Pharmacol. 2010 Jun;50(6):647-58. doi: 10.1177/0091270009349379. Epub 2010 Feb 9. [Article]
- Cerrada-Gimenez M, Weisell J, Hyvonen MT, Park MH, Alhonen L, Vepsalainen J, Keinanen TA: Complex N-acetylation of triethylenetetramine. Drug Metab Dispos. 2011 Dec;39(12):2242-9. doi: 10.1124/dmd.111.041798. Epub 2011 Aug 30. [Article]
- Kodama H, Murata Y, Iitsuka T, Abe T: Metabolism of administered triethylene tetramine dihydrochloride in humans. Life Sci. 1997;61(9):899-907. [Article]
- Lu J: Triethylenetetramine pharmacology and its clinical applications. Mol Cancer Ther. 2010 Sep;9(9):2458-67. doi: 10.1158/1535-7163.MCT-10-0523. Epub 2010 Jul 26. [Article]
Drug created at September 14, 2010 16:21 / Updated at February 20, 2024 23:55