Identification
- Summary
Trimetazidine is a piperazine derivative indicated as an adjunct therapy in symptomatic treatment of stable angina pectoris.
- Generic Name
- Trimetazidine
- DrugBank Accession Number
- DB09069
- Background
Trimetazidine is a piperazine derivative indicated for the symptomatic treatment of stable angina pectoris in patients inadequately controlled or intolerant to first line therapies.9 Trimetazidine has been studied as a treatment for angina pectoris since the late 1960s.7,8
Acidic conditions, caused by anaerobic metabolism and fatty acid oxidation, in response to myocardial ischemia, activate sodium-hydrogen and sodium-calcium antiport systems.5 The increased intracellular calcium decreases contractility.5 It is hypothesized that trimetazidine inhibits 3-ketoacyl coenzyme A thiolase, which decreases fatty acid oxidation but not glucose metabolism, preventing the acidic conditions that exacerbate ischemic injury.1,10 However, evidence for this mechanism is controversial.5
Trimetazidine is not FDA approved. However, it has been approved in France since 1978.10
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Trimetazidine (DB09069)
- Weight
- Average: 266.341
Monoisotopic: 266.163042576 - Chemical Formula
- C14H22N2O3
- Synonyms
- 1-[2,3,4-trimethoxybenzyl] piperazine dihydrochloride
- Trimetazidina
- Trimetazidine
- External IDs
- 40045
Pharmacology
- Indication
Trimetazidine is indicated for the symptomatic treatment of stable angina pectoris in patients inadequately controlled or intolerant to first line therapies.9
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of Angina pectoris •••••••••••• •••••• Treatment of Angina pectoris •••••••••••• Treatment of Angina pectoris •••••••••••• ••••••• •••••••• ••••••• Used as adjunct in combination for symptomatic treatment of Chronic stable angina pectoris •••••••••••• ••••• •••••••••• •• •• •••••••••• •• ••••• ••••••••• Treatment of Tinnitus •••••••••••• •••••• - Contraindications & Blackbox Warnings
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Trimetazidine is indicated for the symptomatic treatment of stable angina pectoris in patients inadequately controlled or intolerant to first line therapies.9 Patients should be counselled regarding the risk of use with reduced renal or hepatic function, worsening of extrapyramidal symptoms or other movement disorders, and risk of falls.10
- Mechanism of action
During myocardial ischemia, anaerobic metabolism takes over, increasing levels of lactic acid.5 The decreased intracellular pH and increased concentration of protons activates sodium-hydrogen and sodium-calcium antiport systems, raising intracellular calcium concentrations, finally leading to decreased contractility.5
This injury to the myocardium raises concentrations of catecholamines, which activate hormone sensitive lipase, and increasing fatty acid concentrations in plasma.5 When the myocardium is repurfused, fatty acid oxidation becomes the dominant form of ATP production, maintaining an acidic pH, and further exacerbating the injury.5
The mechanism of action of trimetazidine is not fully understood.5 Trimetazidine may inhibit mitochondrial 3-ketoacyl coenzyme A thiolase, decreasing long chain fatty acid β-oxidation but not glycolysis in the myocardium.1,10 The decreased long chain fatty acid β-oxidation is compensated for by increased use of glucose, preventing a lowered myocardial pH, and further decreases in contractility.1,10 However, another study suggests that 3-ketoacyl coenzyme A thiolase may not be trimetazidine's target, and that this mechanism may be incorrect.5
Target Actions Organism U3-ketoacyl-CoA thiolase, mitochondrial inhibitorHumans - Absorption
In elderly patients, a 35 mg oral modified release tablet reaches a mean Cmax of 115 µg/L, with a Tmax of 2.0-5.0 hours, and a mean AUC0-12 of 1104 h*µg/L.3 In young, healthy patients, the same dose reaches a mean Cmax of 91.2 µg/L, with a Tmax of 2.0-6.0 hours, and an AUC0-12h 720 h*µg/L.3
- Volume of distribution
The volume of distribution of trimetazidine is 4.8 L/kg.9
- Protein binding
Trimetazidine is 15% protein bound in plasma.3,9 Trimetazidine can bind to human serum albumin.4
- Metabolism
Trimetazidine can be oxidized at the piperazine ring to form trimetazidine ketopiperazine.6 Trimetazidine can also be N-formylated, N-acetylated, or N-methylated at the piperazine ring to form N-formyltrimetazidine, N-acetyltrimetazidine, and N-methyltrimetazidine respectively.6 Alternatively, trimetazidine can be demethylated at the 2, 3, or 4 position of the 2,3,4-trimethoxybenzyl moiety to form 2-desmethyltrimetazidine, 3-desmethyltrimetazidine, or 4-desmethyltrimetazidine.6 The desmethyltrimetazidine metabolites can undergo sulfate conjugation or glucuronidation prior to elimination.6
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- Route of elimination
Trimetazidine is 79-84% eliminated in the urine, with 60% as the unchanged parent compound.3,9 In a study of 4 healthy subjects, individual metabolites made up 0.01-1.4% of the dose recovered in urine.6 In the urine, 2-desmethyltrimetazidine made up 0-1.4% of the recovered dose, 3- and 4-desmethyltrimetazidine made up 0.039-0.071% each, N-methyltrimetazidine made up 0.015-0.11%, trimetazidine ketopiperazine made up 0.011-0.4%, N-formyltrimetazidine made up 0.035-0.42%, N-acetyltrimetazidine made up 0.016-0.19%, desmethyl trimetazidine O-sulphate made up 0.01-0.65%, and an unknown metabolite made up0.026-0.67%.6
- Half-life
In young, healthy subjects, the half life of trimetazidine is 7.81 hours.3,9 In patients over 65, the half life increases to 11.7 hours.3,9
- Clearance
Trimetazidine clearance is strongly correlated with creatinine clearance.9 In eldery patients with a creatinine clearance of 72 ± 8 mL/min, trimetazidine clearance was 15.69 L/h.3 In young, healthy patients with a creatinine clearance of 134 ± 18 mL/min, trimetazidine clearance was 25.2 L/h.3
- Adverse Effects
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Data regarding overdoses of trimetazidine are not readily available.9 Treat overdoses with symptomatic and supportive therapy.9
The oral LD50 in rats is 1700 mg/kg, and in mice is 1550 mg/kg.11 The subcutaneous LD50 in rats is 1500 mg/kg, and in mice is 410 mg/kg.11
- 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.
Drug Interaction Integrate drug-drug
interactions in your softwareMetoclopramide The risk or severity of adverse effects can be increased when Metoclopramide is combined with Trimetazidine. - Food Interactions
- Take with food. Take during a meal.
- Take with plain water. Take with a glass of water.
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 Trimetazidine dihydrochloride 48V6723Z1P 13171-25-0 VYFLPFGUVGMBEP-UHFFFAOYSA-N - International/Other Brands
- Vastarel MR (Laboratoires Servier)
- Over the Counter Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image ไซดีน Tablet, film coated 20 mg Oral บริษัท สหแพทย์เภสัช จำกัด 2009-10-30 Not applicable Thailand 
Categories
- ATC Codes
- C01EB15 — Trimetazidine
- Drug Categories
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as phenylmethylamines. These are compounds containing a phenylmethtylamine moiety, which consists of a phenyl group substituted by an methanamine.
- Kingdom
- Organic compounds
- Super Class
- Benzenoids
- Class
- Benzene and substituted derivatives
- Sub Class
- Phenylmethylamines
- Direct Parent
- Phenylmethylamines
- Alternative Parents
- Phenoxy compounds / Methoxybenzenes / Benzylamines / Anisoles / N-alkylpiperazines / Aralkylamines / Alkyl aryl ethers / Trialkylamines / Dialkylamines / Azacyclic compounds show 2 more
- Substituents
- 1,4-diazinane / Alkyl aryl ether / Amine / Anisole / Aralkylamine / Aromatic heteromonocyclic compound / Azacycle / Benzylamine / Ether / Hydrocarbon derivative show 16 more
- Molecular Framework
- Aromatic heteromonocyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Not Available
Chemical Identifiers
- UNII
- N9A0A0R9S8
- CAS number
- 5011-34-7
- InChI Key
- UHWVSEOVJBQKBE-UHFFFAOYSA-N
- InChI
- InChI=1S/C14H22N2O3/c1-17-12-5-4-11(13(18-2)14(12)19-3)10-16-8-6-15-7-9-16/h4-5,15H,6-10H2,1-3H3
- IUPAC Name
- 1-[(2,3,4-trimethoxyphenyl)methyl]piperazine
- SMILES
- COC1=C(OC)C(OC)=C(CN2CCNCC2)C=C1
References
- General References
- Kantor PF, Lucien A, Kozak R, Lopaschuk GD: The antianginal drug trimetazidine shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation by inhibiting mitochondrial long-chain 3-ketoacyl coenzyme A thiolase. Circ Res. 2000 Mar 17;86(5):580-8. [Article]
- Reymond F, Steyaert G, Carrupt PA, Morin D, Tillement JP, Girault HH, Testa B: The pH-partition profile of the anti-ischemic drug trimetazidine may explain its reduction of intracellular acidosis. Pharm Res. 1999 May;16(5):616-24. [Article]
- Barre J, Ledudal P, Oosterhuis B, Brakenhoff JP, Wilkens G, Sollie FA, Tran D: Pharmacokinetic profile of a modified release formulation of trimetazidine (TMZ MR 35 mg) in the elderly and patients with renal failure. Biopharm Drug Dispos. 2003 May;24(4):159-64. [Article]
- Sun S, Long C, Tao C, Meng S, Deng B: Ultrasonic microdialysis coupled with capillary electrophoresis electrochemiluminescence study the interaction between trimetazidine dihydrochloride and human serum albumin. Anal Chim Acta. 2014 Dec 3;851:37-42. doi: 10.1016/j.aca.2014.08.012. Epub 2014 Aug 13. [Article]
- MacInnes A, Fairman DA, Binding P, Rhodes Ja, Wyatt MJ, Phelan A, Haddock PS, Karran EH: The antianginal agent trimetazidine does not exert its functional benefit via inhibition of mitochondrial long-chain 3-ketoacyl coenzyme A thiolase. Circ Res. 2003 Aug 8;93(3):e26-32. doi: 10.1161/01.RES.0000086943.72932.71. Epub 2003 Jul 17. [Article]
- Jackson PJ, Brownsill RD, Taylor AR, Resplandy G, Walther B, Schwietert HR: Identification of trimetazidine metabolites in human urine and plasma. Xenobiotica. 1996 Feb;26(2):221-8. doi: 10.3109/00498259609046702. [Article]
- Mehrotra TN, Bassadone ET: Trimetazidine in the treatment of angina pectoris. Br J Clin Pract. 1967 Nov 11;21(11):553-4. [Article]
- Brodbin P, O'Connor CA: Trimetazidine in the treatment of angina pectoris. Br J Clin Pract. 1968 Sep;22(9):395-6. [Article]
- Icelandic Medicines Agency: Trimetazidine Oral Modified Release Tablets (Summary of Product Characteristics) [Link]
- EMA Assessment Report: Trimetazidine Containing Medicinal Products [Link]
- Cayman Chemical: Trimetazidine MSDS [Link]
- External Links
- KEGG Drug
- D01606
- PubChem Compound
- 21109
- PubChem Substance
- 310265002
- ChemSpider
- 19853
- BindingDB
- 80613
- 10826
- ChEBI
- 94789
- ChEMBL
- CHEMBL203266
- ZINC
- ZINC000019358638
- Drugs.com
- Drugs.com Drug Page
- Wikipedia
- Trimetazidine
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 4 Completed Treatment Coronary Artery Disease (CAD) / Microcirculation / Vascular Resistance 1 4 Completed Treatment Coronary Artery Disease (CAD) / Type 2 Diabetes Mellitus 1 4 Not Yet Recruiting Treatment Chinese Herbal Medicine / Coronary Heart Disease (CHD) / Unstable Angina Pectoris 1 4 Recruiting Prevention Acute Kidney Injury (AKI) 1 4 Recruiting Treatment Mitochondrial Pathology / Transthyretin Amyloid Cardiopathy 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet, film coated, extended release Oral Tablet Oral Tablet Oral 35.0000 mg Capsule Oral 40.000 mg Tablet, film coated, extended release Oral 35 mg Tablet, film coated Oral Tablet, extended release Oral 35 mg Tablet, extended release Oral Capsule, extended release Oral Tablet, coated Oral Tablet, coated Oral 35 mg Tablet, film coated Oral 35 mg Capsule, extended release Oral 80 mg Tablet, delayed release Oral 35 mg Capsule Oral 80 mg Tablet, coated Oral 20 mg Tablet, film coated Oral 20 mg - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
Property Value Source logP 1.04 Reymond F, Steyaert G, Carrupt PA, Morin D, Tillement JP, Girault HH, Testa B. (1999). The pH-partition profile of the anti-ischemic drug trimetazidine may explain its reduction of intracellular acidosis. Pharm Res; 16(5):616-24. pKa pKa1= 4.45 ± 0.02 and pKa2= 9.14 ± 0.02 Reymond F, Steyaert G, Carrupt PA, Morin D, Tillement JP, Girault HH, Testa B. (1999). The pH-partition profile of the anti-ischemic drug trimetazidine may explain its reduction of intracellular acidosis. Pharm Res; 16(5):616-24. - Predicted Properties
Property Value Source Water Solubility 0.754 mg/mL ALOGPS logP 0.85 ALOGPS logP 0.91 Chemaxon logS -2.6 ALOGPS pKa (Strongest Basic) 9.21 Chemaxon Physiological Charge 1 Chemaxon Hydrogen Acceptor Count 5 Chemaxon Hydrogen Donor Count 1 Chemaxon Polar Surface Area 42.96 Å2 Chemaxon Rotatable Bond Count 5 Chemaxon Refractivity 74.75 m3·mol-1 Chemaxon Polarizability 29.15 Å3 Chemaxon Number of Rings 2 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter Yes 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]- 161.28976 predictedDeepCCS 1.0 (2019) [M+H]+ 163.64777 predictedDeepCCS 1.0 (2019) [M+Na]+ 169.74092 predictedDeepCCS 1.0 (2019)
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- Curator comments
- The identity of trimetazidine's target is controversial.
- General Function
- In the production of energy from fats, this is one of the enzymes that catalyzes the last step of the mitochondrial beta-oxidation pathway, an aerobic process breaking down fatty acids into acetyl-CoA (Probable). Using free coenzyme A/CoA, catalyzes the thiolytic cleavage of medium- to long-chain unbranched 3-oxoacyl-CoAs into acetyl-CoA and a fatty acyl-CoA shortened by two carbon atoms (Probable). Also catalyzes the condensation of two acetyl-CoA molecules into acetoacetyl-CoA and could be involved in the production of ketone bodies (Probable). Also displays hydrolase activity on various fatty acyl-CoAs (PubMed:25478839). Thereby, could be responsible for the production of acetate in a side reaction to beta-oxidation (Probable). Abolishes BNIP3-mediated apoptosis and mitochondrial damage (PubMed:18371312).
- Specific Function
- Acetyl-coa c-acetyltransferase activity
- Gene Name
- ACAA2
- Uniprot ID
- P42765
- Uniprot Name
- 3-ketoacyl-CoA thiolase, mitochondrial
- Molecular Weight
- 41923.82 Da
References
- Lopaschuk GD: Optimizing cardiac energy metabolism: how can fatty acid and carbohydrate metabolism be manipulated? Coron Artery Dis. 2001 Feb;12 Suppl 1:S8-11. [Article]
- Pogatsa G: Metabolic energy metabolism in diabetes: therapeutic implications. Coron Artery Dis. 2001 Feb;12 Suppl 1:S29-33. [Article]
- Kantor PF, Lucien A, Kozak R, Lopaschuk GD: The antianginal drug trimetazidine shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation by inhibiting mitochondrial long-chain 3-ketoacyl coenzyme A thiolase. Circ Res. 2000 Mar 17;86(5):580-8. [Article]
- Chierchia SL: Dobutamine stress echocardiography and the effects of trimetazidine on left ventricular dysfunction in patients with coronary artery disease. Coron Artery Dis. 2001 Feb;12 Suppl 1:S19-21. [Article]
- Dezsi CA: Trimetazidine in Practice: Review of the Clinical and Experimental Evidence. Am J Ther. 2016 May-Jun;23(3):e871-9. doi: 10.1097/MJT.0000000000000180. [Article]
- MacInnes A, Fairman DA, Binding P, Rhodes Ja, Wyatt MJ, Phelan A, Haddock PS, Karran EH: The antianginal agent trimetazidine does not exert its functional benefit via inhibition of mitochondrial long-chain 3-ketoacyl coenzyme A thiolase. Circ Res. 2003 Aug 8;93(3):e26-32. doi: 10.1161/01.RES.0000086943.72932.71. Epub 2003 Jul 17. [Article]
Carriers
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Binder
- General Function
- Toxic substance binding
- Specific Function
- Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
- Gene Name
- ALB
- Uniprot ID
- P02768
- Uniprot Name
- Serum albumin
- Molecular Weight
- 69365.94 Da
References
- Sun S, Long C, Tao C, Meng S, Deng B: Ultrasonic microdialysis coupled with capillary electrophoresis electrochemiluminescence study the interaction between trimetazidine dihydrochloride and human serum albumin. Anal Chim Acta. 2014 Dec 3;851:37-42. doi: 10.1016/j.aca.2014.08.012. Epub 2014 Aug 13. [Article]
Drug created at May 12, 2015 21:45 / Updated at December 02, 2023 07:01