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
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
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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Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

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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Toxicity

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
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
AbacavirAbacavir may decrease the excretion rate of Triethylenetetramine which could result in a higher serum level.
AceclofenacAceclofenac may decrease the excretion rate of Triethylenetetramine which could result in a higher serum level.
AcemetacinAcemetacin may decrease the excretion rate of Triethylenetetramine which could result in a higher serum level.
AcetaminophenAcetaminophen may decrease the excretion rate of Triethylenetetramine which could result in a higher serum level.
AcetazolamideThe excretion of Triethylenetetramine can be increased when combined with Acetazolamide.
Acetylsalicylic acidAcetylsalicylic acid may decrease the excretion rate of Triethylenetetramine which could result in a higher serum level.
AclidiniumTriethylenetetramine may decrease the excretion rate of Aclidinium which could result in a higher serum level.
AcrivastineTriethylenetetramine may decrease the excretion rate of Acrivastine which could result in a higher serum level.
AcyclovirAcyclovir may decrease the excretion rate of Triethylenetetramine which could result in a higher serum level.
Adefovir dipivoxilAdefovir dipivoxil may decrease the excretion rate of Triethylenetetramine which could result in a higher serum level.
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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

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Product Ingredients
IngredientUNIICASInChI Key
Trientine hydrochlorideHC3NX5458238260-01-4WYHIICXRPHEJKI-UHFFFAOYSA-N
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
CufenceCapsule200 mgOralUnivar Solutions Bv2020-12-16Not applicableEU flag
CupriorTablet, film coated150 mgOralGmp Orphan Sa2020-12-16Not applicableEU flag
CupriorTablet, film coated150 mgOralGmp Orphan Sa2020-12-16Not applicableEU flag
SyprineCapsule250 mg/1OralAton Pharma, Inc.1985-11-082016-08-26US flag
SyprineCapsule250 mg/1OralMerck Sharp & Dohme Limited1985-11-082008-03-31US flag
SyprineCapsule250 mg/1OralBausch Health US LLC1985-11-08Not applicableUS flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Mar-trientineCapsule250 mgOralMarcan Pharmaceuticals Inc2020-11-10Not applicableCanada flag
Trientine HydrochlorideCapsule250 mg/1OralOceanside Pharmaceutials2018-02-09Not applicableUS flag
Trientine hydrochlorideCapsule250 mg/1OralMsn Laboratories Private Limited2019-05-22Not applicableUS flag
Trientine HydrochlorideCapsule250 mg/1OralNavinta Llc2020-12-05Not applicableUS flag
Trientine HydrochlorideCapsule250 mg/1OralLannett Company Inc.2020-12-22Not applicableUS flag
Trientine HydrochlorideCapsule250 mg/1OralRising Pharma Holdings, Inc.2021-03-30Not applicableUS flag
Trientine HydrochlorideCapsule250 mg/1OralBluepharma - Industria Farmaceutica, S.A.2019-06-01Not applicableUS flag
Trientine hydrochlorideCapsule250 mg/1OralRising Pharmaceuticals, Inc.2020-02-20Not applicableUS flag
Trientine HydrochlorideCapsule, gelatin coated250 mg/1OralAmneal Pharmaceuticals NY LLC2019-02-08Not applicableUS flag
Trientine hydrochlorideCapsule250 mg/1OralCadila Healthcare Limited2019-04-29Not applicableUS flag

Categories

ATC Codes
A16AX12 — Trientine
Drug Categories
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
  1. 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]
  2. 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]
  3. 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]
  4. 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]
  5. 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]
  6. 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]
  7. 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]
  8. FDA Approved Drug Products: CUVRIOR (trientine tetrahydrochloride) tablets, for oral use [Link]
  9. CDH Chemicals: Triethylenetetramine MSDS [Link]
KEGG Compound
C07166
PubChem Compound
5565
PubChem Substance
310264897
ChemSpider
21106175
BindingDB
50323751
RxNav
10798
ChEBI
39501
ChEMBL
CHEMBL609
ZINC
ZINC000019364225
PDBe Ligand
104
Wikipedia
Triethylenetetramine
PDB Entries
1dj6
MSDS
Download (48.7 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Unknown StatusTreatmentWilsons Disease1
3CompletedTreatmentWilsons Disease1
2RecruitingTreatmentHypertrophic Cardiomyopathy (HCM)1
2WithdrawnPreventionMacular Edema Following Cataract Surgery1
1CompletedTreatmentCancer, Advanced1
1CompletedTreatmentWilsons Disease1
1WithdrawnTreatmentMelanoma1
1, 2CompletedTreatmentFallopian Tubes Cancer / Ovarian neoplasms malignant (excl germ cell) / Primary Peritoneal Cancer1
Not AvailableCompletedNot AvailableTrientine Treatment for Wilson's Disease1
Not AvailableCompletedTreatmentWilsons Disease1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
CapsuleOral200 MG
TabletOral150 MG
Tablet, film coatedOral150 MG
CapsuleOral250 mg
CapsuleOral
CapsuleOral250 mg/1
Capsule, gelatin coatedOral250 mg/1
Prices
Not Available
Patents
Not Available

Properties

State
Liquid
Experimental Properties
PropertyValueSource
melting point (°C)12https://www.cdhfinechemical.com/images/product/msds/37_1605852200_TriethyleneTetramine-CASNO-112-24-3-MSDS.pdf
boiling point (°C)266-267https://www.cdhfinechemical.com/images/product/msds/37_1605852200_TriethyleneTetramine-CASNO-112-24-3-MSDS.pdf
water solubilitySolublehttps://www.cdhfinechemical.com/images/product/msds/37_1605852200_TriethyleneTetramine-CASNO-112-24-3-MSDS.pdf
Predicted Properties
PropertyValueSource
Water Solubility27.5 mg/mLALOGPS
logP-1.8ALOGPS
logP-2.2ChemAxon
logS-0.73ALOGPS
pKa (Strongest Basic)9.77ChemAxon
Physiological Charge2ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count4ChemAxon
Polar Surface Area76.1 Å2ChemAxon
Rotatable Bond Count7ChemAxon
Refractivity43.32 m3·mol-1ChemAxon
Polarizability18.04 Å3ChemAxon
Number of Rings0ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
GC-MS Spectrum - EI-BGC-MSsplash10-0006-9000000000-dc59b9e5ca78bd735bee
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-QQ , positiveLC-MS/MSsplash10-0002-0900000000-a71c042b9b4739000226
LC-MS/MS Spectrum - LC-ESI-QQ , positiveLC-MS/MSsplash10-000i-9200000000-066d71fec24b87eb78fd
LC-MS/MS Spectrum - LC-ESI-QQ , positiveLC-MS/MSsplash10-0083-9000000000-30cc8480e8680b6fc470
LC-MS/MS Spectrum - LC-ESI-QQ , positiveLC-MS/MSsplash10-0006-9000000000-3467a5c3550b900f122e
LC-MS/MS Spectrum - LC-ESI-QQ , positiveLC-MS/MSsplash10-0006-9000000000-c5b8a993b94560436a51

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
  1. 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]
  2. 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]
  3. Kodama H, Murata Y, Iitsuka T, Abe T: Metabolism of administered triethylene tetramine dihydrochloride in humans. Life Sci. 1997;61(9):899-907. [Article]
  4. 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 August 19, 2022 08:38