Long chain 3-ketoyl coenzyme A thiolase (IC50 = 75 nM); Autophagy; β-oxidation; 3-hydroxyacyl-CoA dehydrogenase (HADHA)

Trimetazidine (1 μM-100 μM; 24 hours; HUVECs) can, in a dose-dependent way, increase the vitality of HUVECs injured by oxidation [1].

Trimetazidine at dosages of 10 mg/kg and 20 mg/kg (5-20 mg/kg; oral; 1 hour; Swiss albino male mice) effectively reduces epilepsy in the increased current electroshock epileptic seizure (ICES) study Threshold current animals [5].

Trimetazidine had no effect on myocardial oxygen consumption or cardiac work under any aerobic perfusion condition used. In hearts perfused with 5 mmol/L glucose and 0.4 mmol/L palmitate, trimetazidine decreased the rate of palmitate oxidation from 488+/-24 to 408+/-15 nmol x g dry weight(-1) x minute(-1) (P<0.05), whereas it increased rates of glucose oxidation from 1889+/-119 to 2378+/-166 nmol x g dry weight(-1) x minute(-1) (P<0.05). In hearts subjected to low-flow ischemia, trimetazidine resulted in a 210% increase in glucose oxidation rates. In both aerobic and ischemic hearts, glycolytic rates were unaltered by trimetazidine. The effects of trimetazidine on glucose oxidation were accompanied by a 37% increase in the active form of pyruvate dehydrogenase, the rate-limiting enzyme for glucose oxidation. No effect of trimetazidine was observed on glycolysis, glucose oxidation, fatty acid oxidation, or active pyruvate dehydrogenase when palmitate was substituted with 0.8 mmol/L octanoate or 1.6 mmol/L butyrate, suggesting that trimetazidine directly inhibits long-chain fatty acid oxidation. This reduction in fatty acid oxidation was accompanied by a significant decrease in the activity of the long-chain isoform of the last enzyme involved in fatty acid beta-oxidation, 3-ketoacyl coenzyme A (CoA) thiolase activity (IC(50) of 75 nmol/L). In contrast, concentrations of trimetazidine in excess of 10 and 100 micromol/L were needed to inhibit the medium- and short-chain forms of 3-ketoacyl CoA thiolase, respectively. Previous studies have shown that inhibition of fatty acid oxidation and stimulation of glucose oxidation can protect the ischemic heart. Therefore, our data suggest that the antianginal effects of trimetazidine may occur because of an inhibition of long-chain 3-ketoacyl CoA thiolase activity, which results in a reduction in fatty acid oxidation and a stimulation of glucose oxidation[3].

Cell viability assay [1]
Cell Types: human umbilical vein endothelial cells (HUVEC)
Tested Concentrations: 1 μM, 10 μM, 100 μM
Incubation Duration: 24 hrs (hours)
Experimental Results: The viability of HUVECs induced by oxidative damage is enhanced.

Animal/Disease Models: Swiss albino male mouse (24-35 g) [4]
Doses: 5 mg/kg, 10 mg/kg and 20 mg/kg; 10 mL/kg body weight
Doses: oral; 1 hour
Experimental Results: at In the ICES test, the 10 mg/kg and 20 mg/kg doses Dramatically increased the epileptic threshold current.

Absorption, Distribution and Excretion
In elderly patients, the mean peak plasma concentration (Cmax) of the 35 mg oral extended-release tablet was 115 µg/L, the time to peak concentration (Tmax) was 2.0–5.0 hours, and the mean AUC0–12 was 1104 hµg/L. In young, healthy patients, the mean peak plasma concentration (Cmax) of the same dose was 91.2 µg/L, the time to peak concentration (Tmax) was 2.0–6.0 hours, and the AUC0–12h was 720 hµg/L. Trimetazidine is excreted in the urine at a rate of 79–84%, of which 60% is the unchanged compound. In a study involving four healthy subjects, the recoveries of various metabolites in the urine accounted for 0.01–1.4% of the total dose. In urine, 2-demethyltrimetazidine accounted for 0-1.4% of the recovered dose, 3- and 4-demethyltrimetazidine each accounted for 0.039-0.071%, N-methyltrimetazidine for 0.015-0.11%, trimetazidine-ketopiperazine for 0.011-0.4%, N-formyltrimetazidine for 0.035-0.42%, N-acetyltrimetazidine for 0.016-0.19%, demethyltrimetazidine O-sulfate for 0.01-0.65%, and an unknown metabolite for 0.026-0.67%. The volume of distribution of trimetazidine is 4.8 L/kg. The clearance of trimetazidine is closely related to creatinine clearance. In elderly patients with a creatinine clearance of 72 ± 8 mL/min, the clearance of trimetazidine was 15.69 L/h. In young, healthy patients with a creatinine clearance of 134 ± 18 mL/min, trimetazidine clearance was 25.2 L/h. Metabolic/Metabolic Substances Trimetazidine can be oxidized on the piperazine ring to form trimetazidine ketopiperazine. Trimetazidine can also be N-formylated, N-acetylated, or N-methylated on the piperazine ring to form N-formyltrimetazidine, N-acetyltrimetazidine, and N-methyltrimetazidine, respectively. Furthermore, trimetazidine can undergo demethylation at the 2, 3, or 4 position of the 2,3,4-trimethoxybenzyl moiety to form 2-demethyltrimetazidine, 3-demethyltrimetazidine, or 4-demethyltrimetazidine. Demethyltrimetazidine metabolites may undergo sulfate conjugation or glucuronidation before elimination. Biological Half-Life In young, healthy subjects, the half-life of trimetazidine was 7.81 hours. In patients aged 65 and older, the half-life was prolonged to 11.7 hours.

Protein Binding
Trimetazidine has a 15% protein binding rate in plasma. Trimetazidine can bind to human serum albumin.

[1]. Protective effects of trimetazidine against vascular endothelial cell injury induced by oxidation. Journal of Geriatric Cardiology, December 2008 , Vol 5 No 4.

[2]. Defining the role of trimetazidine in the treatment of cardiovascular disorders: some insights on its role in heart failure and peripheral artery disease. Drugs. 2014 Jun;74(9):971-80.

[3]. 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.

[4]. Inhibition of Fatty Acid Oxidation Modulates Immunosuppressive Functions of Myeloid-Derived Suppressor Cells and Enhances Cancer Therapies. Cancer Immunol Res. 2015 Nov;3(11):1236-47.

[5]. Trimetazidine exerts protection against increasing current electroshock seizure test in mice. Seizure. 2010 Jun;19(5):300-2.

1-[(2,3,4-trimethoxyphenyl)methyl]piperazine is an aromatic amine. Trimetazine is a piperazine derivative indicated for symptomatic treatment of patients with poorly controlled or intolerant stable angina as first-line therapy. Trimetazine has been investigated for the treatment of angina since the late 1960s. Anaerobic metabolism and fatty acid oxidation caused by myocardial ischemia create an acidic environment, activating the sodium-hydrogen and sodium-calcium antitransport systems. Increased intracellular calcium ion concentration reduces myocardial contractility. It is hypothesized that trimetazine inhibits 3-ketoyl-CoA thiolase, thereby reducing fatty acid oxidation without affecting glucose metabolism, preventing the acidic environment that exacerbates ischemic injury. However, evidence for this mechanism remains controversial. Trimetazine has not yet been approved by the U.S. Food and Drug Administration (FDA). However, it has been approved in France since 1978. Trimetazine is an orally administered small molecule compound with anti-ischemic, potential immunomodulatory, and antitumor properties. Although its exact mechanism is not fully elucidated, it is speculated that trimetazidine selectively inhibits long-chain 3-ketoyl-CoA thiolase (LC 3-KAT), the last enzyme in the free fatty acid (FFA) β-oxidation pathway. This stimulates glucose oxidation, which requires less oxygen and cellular energy than the β-oxidation process. This may optimize myocardial energy metabolism and cardiac function under ischemic conditions. In cancer cells, inhibition of fatty acid oxidation (FAO) alters the metabolic processes required for tumor cell function and proliferation, thereby inducing tumor cell apoptosis. Furthermore, inhibition of fatty acid oxidation (FAO) may block the immunosuppressive function of myeloid-derived suppressor cells (MSDCs), which are thought to promote malignant cell proliferation and migration by inhibiting T cell function.
A vasodilator used to treat exertional angina or ischemic heart disease.

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Drug Indications
Trimetazidine is indicated for the symptomatic treatment of patients with stable angina who are poorly controlled or intolerant to first-line therapy.

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Mechanism of Action
During myocardial ischemia, anaerobic metabolism takes over, leading to elevated lactate levels. Decreased intracellular pH and increased proton concentration activate the sodium-hydrogen and sodium-calcium antitransport systems, increasing intracellular calcium concentration and ultimately causing a decrease in myocardial contractility. Myocardial injury increases catecholamine concentrations, activates hormone-sensitive lipases, and increases plasma fatty acid concentrations. Upon myocardial reperfusion, fatty acid oxidation becomes the primary mode of ATP production, maintaining an acidic pH and further exacerbating the injury. The mechanism of action of trimetazidine is not fully elucidated. Trimetazidine may inhibit mitochondrial 3-ketoyl-CoA thiolytic enzyme, reducing β-oxidation of long-chain fatty acids in the myocardium, but without affecting glycolysis. The reduction in long-chain fatty acid β-oxidation can be compensated for by increased glucose utilization, thereby preventing a decrease in myocardial pH and avoiding further decline in myocardial contractility. However, another study suggests that 3-ketoyl-CoA thiolytic enzyme may not be a target of trimetazidine, and this mechanism may not be accurate.

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Pharmacodynamics
Trimetazidine is indicated for the symptomatic treatment of stable angina that is poorly controlled or intolerant of first-line therapy. Patients should be informed of the risks associated with this medication, including impaired renal or hepatic function, worsening of extrapyramidal symptoms or other movement disorders, and the risk of falls.

C14H24CL2N2O3

339.2580

338.116

C, 49.57; H, 7.13; Cl, 20.90; N, 8.26; O, 14.15

13171-25-0

Trimetazidine;5011-34-7;Trimetazidine-d8 dihydrochloride;1219795-37-5

21109

White to off-white solid powder

364ºC at 760 mmHg

231-235 °C(lit.)

174ºC

1.73E-05mmHg at 25°C

2.988

1

5

5

19

259

0

VYFLPFGUVGMBEP-UHFFFAOYSA-N

InChI=1S/C14H22N2O3.2ClH/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;2*1H

1-[(2,3,4-trimethoxyphenyl)methyl]piperazine;dihydrochloride

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

H2O : ≥ 100 mg/mL (~294.76 mM)
DMSO : ~25 mg/mL (~73.69 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (7.37 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (7.37 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: 100 mg/mL (294.76 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)