- Accession Number
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.
- Small Molecule
- Approved, Investigational
- Average: 146.2339
- Chemical Formula
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
- Contraindications & Blackbox Warnings
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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.
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
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.
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- 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.
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.
- Not Available
- Adverse Effects
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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
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
- 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.
Drug Interaction Abacavir Abacavir may decrease the excretion rate of Triethylenetetramine which could result in a higher serum level. Acarbose Acarbose 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. Acetylsalicylic acid Acetylsalicylic acid may decrease the excretion rate of Triethylenetetramine which could result in a higher serum level. Aclidinium Triethylenetetramine may decrease the excretion rate of Aclidinium which could result in a higher serum level. Acrivastine Triethylenetetramine may decrease the excretion rate of Acrivastine which could result in a higher serum level. Acyclovir Acyclovir may decrease the excretion rate of Triethylenetetramine which could result in a higher serum level.Additional Data Available
- Extended DescriptionExtended Description
Extended description of the mechanism of action and particular properties of each drug interaction.Learn more
A severity rating for each drug interaction, from minor to major.Learn more
- Evidence LevelEvidence Level
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An effect category for each drug interaction. Know how this interaction affects the subject drug.Learn more
- Food Interactions
- Take at least 2 hours before or after iron supplements. Iron and triethylenetetramine inhibit each others absorption.
- Take on an empty stomach. Take triethylenetetramine one hour before or two hours after eating a meal or at least one hour of separation from other drugs, milk, or food.
- Product Ingredients
Ingredient UNII CAS InChI Key Trientine hydrochloride HC3NX54582 38260-01-4 WYHIICXRPHEJKI-UHFFFAOYSA-N
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Syprine Capsule 250 mg/1 Oral Aton Pharma, Inc. 1985-11-08 2016-08-26 Syprine Capsule 250 mg/1 Oral Merck Sharp & Dohme Limited 1985-11-08 2008-03-31 Syprine Capsule 250 mg/1 Oral Bausch Health US LLC 1985-11-08 Not applicable
- Generic Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Trientine hydrochloride Capsule 250 mg/1 Oral Novadoz Pharmaceuticals Llc 2019-05-22 Not applicable Trientine Hydrochloride Capsule 250 mg/1 Oral Dr.Reddys Laboratories Inc 2019-07-03 Not applicable Trientine Hydrochloride Capsule 250 mg/1 Oral Par Pharmaceutical, Inc. 2019-09-27 Not applicable Trientine Hydrochloride Capsule 250 mg/1 Oral Navinta Llc 2019-03-01 Not applicable Trientine hydrochloride Capsule 250 mg/1 Oral Msn Laboratories Private Limited 2019-05-22 Not applicable Trientine hydrochloride Capsule 250 mg/1 Oral Rising Pharmaceuticals, Inc. 2020-02-20 Not applicable Trientine Hydrochloride Capsule 250 mg/1 Oral Oceanside Pharmaceutials 2018-02-09 Not applicable Trientine hydrochloride Capsule 250 mg/1 Oral Cadila Healthcare Limited 2019-04-29 Not applicable Trientine Hydrochloride Capsule 250 mg/1 Oral Lannett Company Inc. 2019-09-10 Not applicable Trientine Hydrochloride Capsule 250 mg/1 Oral Actavis Pharma Company 2018-02-08 Not applicable
- ATC Codes
- A16AX12 — Trientine
- Drug Categories
- Alimentary Tract and Metabolism
- Chelating Agents
- Compounds used in a research, industrial, or household setting
- Drugs that are Mainly Renally Excreted
- Metal Chelating Activity
- Metal Chelator
- Sequestering Agents
- Various Alimentary Tract and Metabolism Products
- Chemical TaxonomyProvided by Classyfire
- 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.
- Organic compounds
- Super Class
- Organic nitrogen compounds
- Organonitrogen compounds
- Sub Class
- Direct Parent
- Alternative Parents
- Organopnictogen compounds / Monoalkylamines / Hydrocarbon derivatives
- 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)
- CAS number
- InChI Key
- IUPAC Name
- 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. [PubMed:19602718]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- PDB Entries
- Download (48.7 KB)
- Clinical Trials
Phase Status Purpose Conditions Count 4 Active Not Recruiting Treatment Wilson's Disease 1 3 Completed Treatment Wilson's Disease 1 2 Withdrawn Prevention Macular Edema Following Cataract Surgery 1 1 Completed Treatment Advanced Cancers 1 1 Completed Treatment Wilson's Disease 1 1 Withdrawn Treatment Melanoma 1 Not Available Completed Not Available Trientine Treatment for Wilson's Disease 1 Not Available Completed Treatment Wilson's Disease 1 Not Available Terminated Not Available Diabetic Retinopathy (DR) 1
- Not Available
- Not Available
- Dosage Forms
Form Route Strength Capsule Oral 200 MG Tablet Oral 150 MG Capsule 250 mg Capsule Oral 250 mg/1 Capsule, gelatin coated Oral 250 mg/1
- Not Available
- Not Available
- Experimental Properties
Property Value Source melting point (°C) 12 MSDS boiling point (°C) 266 MSDS water solubility Soluble MSDS
- 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 3 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
- Mass Spec (NIST)
- Not Available
- Bos taurus
- Pharmacological action
- 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
- Uniprot ID
- Uniprot Name
- Molecular Weight
- 61006.81 Da
- 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 June 12, 2020 11:42