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
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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Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

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

TargetActionsOrganism
U3-ketoacyl-CoA thiolase, mitochondrial
inhibitor
Humans
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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Toxicity

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.
DrugInteraction
MetoclopramideThe risk or severity of adverse effects can be increased when Metoclopramide is combined with Trimetazidine.
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Food Interactions
  • Take with food. Take during a meal.
  • Take with plain water. Take with a glass of water.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Trimetazidine dihydrochloride48V6723Z1P13171-25-0VYFLPFGUVGMBEP-UHFFFAOYSA-N
International/Other Brands
Vastarel MR (Laboratoires Servier)
Over the Counter Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
ไซดีนTablet, film coated20 mgOralบริษัท สหแพทย์เภสัช จำกัด2009-10-30Not applicableThailand flag

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
  1. 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]
  2. 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]
  3. 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]
  4. 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]
  5. 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]
  6. 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]
  7. Mehrotra TN, Bassadone ET: Trimetazidine in the treatment of angina pectoris. Br J Clin Pract. 1967 Nov 11;21(11):553-4. [Article]
  8. Brodbin P, O'Connor CA: Trimetazidine in the treatment of angina pectoris. Br J Clin Pract. 1968 Sep;22(9):395-6. [Article]
  9. Icelandic Medicines Agency: Trimetazidine Oral Modified Release Tablets (Summary of Product Characteristics) [Link]
  10. EMA Assessment Report: Trimetazidine Containing Medicinal Products [Link]
  11. Cayman Chemical: Trimetazidine MSDS [Link]
KEGG Drug
D01606
PubChem Compound
21109
PubChem Substance
310265002
ChemSpider
19853
BindingDB
80613
RxNav
10826
ChEBI
94789
ChEMBL
CHEMBL203266
ZINC
ZINC000019358638
Drugs.com
Drugs.com Drug Page
Wikipedia
Trimetazidine

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedTreatmentCoronary Artery Disease (CAD) / Type 2 Diabetes Mellitus1
4Not Yet RecruitingTreatmentChinese Herbal Medicine / Coronary Heart Disease (CHD) / Unstable Angina Pectoris1
4Not Yet RecruitingTreatmentCoronary Heart Disease (CHD) / Diastolic Dysfunction1
4RecruitingTreatmentPercutaneous Coronary Intervention (PCI)1
4Unknown StatusTreatmentCoronary Artery Disease (CAD)2
4Unknown StatusTreatmentCoronary Artery Disease (CAD) / Microcirculation / Vascular Resistance1
3RecruitingPreventionDiabetes Mellitus / Unstable Angina Pectoris1
3RecruitingTreatmentHCC2
2CompletedBasic SciencePlatelet Dysfunction Due to Drugs1
2Not Yet RecruitingTreatmentDiabetic Nephropathy1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Tablet, delayed releaseOral
Tablet, film coated, extended releaseOral
TabletOral
Tablet, film coated, extended releaseOral35 mg
Tablet, film coatedOral
Tablet, extended releaseOral
Capsule, extended releaseOral
Tablet, coatedOral
Tablet, coatedOral35 mg
Tablet, film coatedOral35 mg
Capsule, extended releaseOral80 mg
Tablet, delayed releaseOral35 mg
Capsule80 mg
Tablet, coatedOral20 mg
Tablet, film coatedOral20 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
logP1.04 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.
pKapKa1= 4.45 ± 0.02 and pKa2= 9.14 ± 0.02Reymond 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
PropertyValueSource
Water Solubility0.754 mg/mLALOGPS
logP0.85ALOGPS
logP0.91ChemAxon
logS-2.6ALOGPS
pKa (Strongest Basic)9.21ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area42.96 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity74.75 m3·mol-1ChemAxon
Polarizability29.15 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
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
MS/MS Spectrum - , positiveLC-MS/MSsplash10-014i-2900000000-9af80d4cc6e8d3139dd7

Targets

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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
  1. 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]
  2. Pogatsa G: Metabolic energy metabolism in diabetes: therapeutic implications. Coron Artery Dis. 2001 Feb;12 Suppl 1:S29-33. [Article]
  3. 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]
  4. 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]
  5. 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]
  6. 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
  1. 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 January 02, 2022 12:00