Identification

Name
Triethylenetetramine
Accession Number
DB06824
Type
Small Molecule
Groups
Approved, Investigational
Description

Triethylenetatramine (TETA) is a highly selective divalent Cu(II) chelator and orphan drug that revereses copper overload in tissues. Its salt form, trientine (triethylenetetramine dihydrochloride or 2,2,2-tetramine) was introduced in 1969 as an alternative to D-penicillamine. It consists of a polyamine-like structure different from D-penicillamine, as it lack sulfhydryl groups. It was previously approved by FDA in 1985 as second-line pharmacotherapy for Wilson's disease. Although penicillamine treatment is believed to be more extensive, TETA therapy has been shown to be an effective initial therapy, even with patients with decompensated liver disease at the outset, and prolonged TETA treatment is not associated with adverse effects as expected in penicillamine treatment. Its clinical applications on cancer, diabetes mellitus, Alzheimer's disease and vascular demetia are being studied.

Structure
Thumb
Synonyms
  • TETA
  • Trien
  • Trientine
Product Ingredients
IngredientUNIICASInChI Key
Trientine hydrochlorideHC3NX5458238260-01-4WYHIICXRPHEJKI-UHFFFAOYSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
SyprineCapsule250 mg/1OralMerck Sharp & Dohme Limited1985-11-082008-03-31Us
SyprineCapsule250 mg/1OralValeant Pharmaceuticals North America1985-11-08Not applicableUs
SyprineCapsule250 mg/1OralAton Pharma, Inc.1985-11-082016-08-26Us
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Trientine HydrochlorideCapsule250 mg/1OralOceanside Pharmaceutials2018-02-09Not applicableUs
Trientine HydrochlorideCapsule250 mg/1OralActavis Pharma Company2018-02-08Not applicableUs
Categories
UNII
SJ76Y07H5F
CAS number
112-24-3
Weight
Average: 146.2339
Monoisotopic: 146.153146596
Chemical Formula
C6H18N4
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

Pharmacology

Indication

Trientine is a copper chelator used in the treatment of Wilson's disease as an alternative to D-penicillamine. It tends to be used in patients who are experiencing serious adverse effects from penicillamine therapy or intolerance of penicillamine.

Associated Conditions
Pharmacodynamics

TETA is a selective copper (II) chelator. tightly binds and facilitates systemic elimination of Cu(II) into the urine whilst neutralizing its catalytic activity, but does not cause systemic copper deficiency even after prolonged use. It may also act as an antioxidant as it suppresses the copper-mediated oxidative stress. TETA not only increases urinary Cu excretion, but also decreases intestinal copper absorption by 80%.

Mechanism of action

Copper is chelated by forming a stable complex with the four constituent nitrogens in a planar ring as copper displays enhanced ligand binding properties for nitrogen compared to oxygen. It binds Cu(II) very tightly, having a dissociation constant from Cu(II) of 10^−15 mol/L at pH 7.0 . TETA reacts in a stoichiometric ratio 1:1 with copper and is also able to complex with iron and zinc in vivo. TETA is considered a potential chemotherapeutic agent as it could be a telomerase inhibitor because it is a ligand for G-quadruplex, and stabilizes both intra- and intermolecular G-quadruplexes. It may mediate a selective inhibitory effect or cytotoxicity on tumor growth. Chelating excess copper may affect copper-induced angiogenesis. Other mechanisms of action of TETA for alternative therapeutic implications include improved antioxidant defense against oxidative stress, pro-apoptosis, and reduced inflammation.

Absorption

It is poorly absorbed from the gastrointestinal tract with a bioavailability of 8 to 30% and and what is absorbed is metabolized and inactivated. 5% to 18% that is systemically absorbed in humans is reported to be extensively metabolized [2]. The time to reach peak concentration (Tmax) for humans occur between 0.8 to 4 hours [4].

Volume of distribution

It is widely distributed in tissues with relatively high concentrations measured in liver, heart, and kidney. A recent study reported that the central and peripheral volumes of distribution were 393 L and 252 L, respectively [4].

Protein binding
Not Available
Metabolism

It is mainly metabolized via acetylation, and two major acetylated metabolites exist in human serum and urine. TETA is readily acetylated into N1-acetyltriethylenetetramine (MAT) and N1,N10-diacetyltriethylenetetramine (DAT). MAT is still capable of binding divalent Cu, Fe, and Zn but to a much lesser extent compared to the unchanged drug. To date no enzyme has been definitely identified as responsible for TETA acetylation but spermidine/spermine acetyltransferase-1 (SSAT-1) is a potential candidate responsible for acetylation of TETA because of the close chemical resemblance between its natural substrate spermidine and TETA. TETA is also shown to be a substrate for human thialysine acetyltransferase (SSAT2) in vitro.

Route of elimination

The unchanged drug and two acetylated metabolites, N1-acetyltriethylenetetramine (MAT) and N1,N10-diacetyltriethylenetetramine (DAT), are mainly excreted in the urine. About 1% of the administered trientine and about 8% of the biotransformed trientine metabolite, acetyltrien, ultimately appear in the urine. The amounts of urinary copper, zinc and iron increase in parallel with the amount of trientine excreted in the urine [7]. Unchanged drug is also excreted in feces after oral administration.

Half life

The plasma elimination half life of TETA in healthy volunteers and Wilson's disease patients ranges from 1.3 to 4 hours. The metabolites are expected to be longer than the parent drug.

Clearance
Not Available
Toxicity

Neurological worsening may be associated with TETA therapy. Trientine also chelates iron, and co-administration of trientine and iron should be avoided because the complex with iron is toxic. A reversible sideroblastic anemia may be a consequence of overtreatment and resultant copper deficiency. Lupus-like reactions have also been reported [7]. The oral LD50 value in rats is rat, mouse, rabbit is 2500mg/kg, 1600mg/kg, and 5500mg/kg, respectively.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AcetaminophenAcetaminophen may decrease the excretion rate of Triethylenetetramine which could result in a higher serum level.
Acetylsalicylic acidAcetylsalicylic acid may decrease the excretion rate of Triethylenetetramine which could result in a higher serum level.
AlmasilateAlmasilate can cause a decrease in the absorption of Triethylenetetramine resulting in a reduced serum concentration and potentially a decrease in efficacy.
AloglutamolAloglutamol can cause a decrease in the absorption of Triethylenetetramine resulting in a reduced serum concentration and potentially a decrease in efficacy.
AlprazolamAlprazolam may decrease the excretion rate of Triethylenetetramine which could result in a higher serum level.
AluminiumAluminium can cause a decrease in the absorption of Triethylenetetramine resulting in a reduced serum concentration and potentially a decrease in efficacy.
Aluminium acetoacetateAluminium acetoacetate can cause a decrease in the absorption of Triethylenetetramine resulting in a reduced serum concentration and potentially a decrease in efficacy.
Aluminium glycinateAluminium glycinate can cause a decrease in the absorption of Triethylenetetramine resulting in a reduced serum concentration and potentially a decrease in efficacy.
Aluminum hydroxideAluminum hydroxide can cause a decrease in the absorption of Triethylenetetramine resulting in a reduced serum concentration and potentially a decrease in efficacy.
AmilorideAmiloride may increase the excretion rate of Triethylenetetramine which could result in a lower serum level and potentially a reduction in efficacy.
Food Interactions
Not Available

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. [PubMed:19602718]
  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. [PubMed:20145262]
  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. [PubMed:17108057]
  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. [PubMed:20660601]
  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. [PubMed:21770477]
  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. [PubMed:20221822]
  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. [PubMed:22340672]
External Links
KEGG Compound
C07166
PubChem Compound
5565
PubChem Substance
310264897
ChemSpider
21106175
BindingDB
50323751
ChEBI
39501
ChEMBL
CHEMBL609
HET
104
Wikipedia
Triethylenetetramine
PDB Entries
1dj6
MSDS
Download (48.7 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentAdvanced Cancers1
1WithdrawnTreatmentMelanoma1
2WithdrawnPreventionMacular Edema Following Cataract Surgery1
3CompletedTreatmentWilson's Disease1
Not AvailableCompletedTreatmentWilson's Disease1
Not AvailableNot Yet RecruitingNot AvailableTrientine Treatment for Wilson's Disease1
Not AvailableTerminatedNot AvailableRetinopathy, Diabetic1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
CapsuleOral250 mg/1
Prices
Not Available
Patents
Not Available

Properties

State
Liquid
Experimental Properties
PropertyValueSource
melting point (°C)12MSDS
boiling point (°C)266MSDS
water solubilitySolubleMSDS
Predicted Properties
PropertyValueSource
Water Solubility27.5 mg/mLALOGPS
logP-1.8ALOGPS
logP-2.2ChemAxon
logS-0.73ALOGPS
pKa (Strongest Basic)9.77ChemAxon
Physiological Charge3ChemAxon
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

Taxonomy

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
Secondary aliphatic amine / Organopnictogen compound / Hydrocarbon derivative / Primary amine / Primary aliphatic amine / Aliphatic acyclic compound
Molecular Framework
Aliphatic acyclic compounds
External Descriptors
tetraamine, polyazaalkane (CHEBI:39501)

Transporters

Kind
Protein
Organism
Bos taurus
Pharmacological action
Unknown
Actions
Substrate
General Function
Laminin binding
Specific Function
Cell surface proteoglycan that bears heparan sulfate. Binds, via the heparan sulfate side chains, alpha-4 (V) collagen and participates in Schwann cell myelination (By similarity). May act as a cat...
Gene Name
GPC1
Uniprot ID
G3X745
Uniprot Name
Glypican-1
Molecular Weight
61006.81 Da
References
  1. Belting M, Mani K, Jonsson M, Cheng F, Sandgren S, Jonsson S, Ding K, Delcros JG, Fransson LA: Glypican-1 is a vehicle for polyamine uptake in mammalian cells: a pivital role for nitrosothiol-derived nitric oxide. J Biol Chem. 2003 Nov 21;278(47):47181-9. Epub 2003 Sep 11. [PubMed:12972423]

Drug created on September 14, 2010 10:21 / Updated on August 02, 2018 07:51