Trimetazidine in Blood, Bile, Organs and Urine

Naito, Seiji; Osumi, Seimei; Sekishiro, Kyoko; Hirose, Michiko

doi:10.1248/cpb.20.682

Cited by 14 publications

(6 citation statements)

References 1 publication

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“…The kinetics and metabolism of trimetazidine were studied in mice, rats, and rabbits (30). At 300 to 700 mg/kg, P.o., trimetazidine was shown to be rapidly absorbed and distributed without accumulation in the tissues.…”

Section: Pharm Acokineticsmentioning

confidence: 99%

Trimetazidine, A Cellular Anti‐ischemic Agent

Harpey

Clauser

Labrid

et al. 1988

Cardiovascular Drug Reviews

109

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Trimetazidine (S 50 16), a molecule developed by the Servier Research Institute, is a cellular anti-ischemic agent. Its chemical name is I -(2,3,4-trimethoxybenzyl)-piperazine dihydrochloride (Fig. I ). Initial pharmacological studies have indicated that trimetazidine prevents cellular changes associated with ischemia or hypoxia, but it has no effect under normoxic conditions ( I ,2).Trimetazidine is freely soluble in water (80%), sparingly soluble in methanol, but insoluble in other organic solvents. Trimetazidine solution is slightly sensitive to light although substantially less than dihydropyridines. The molecular weight of tnmetazidine is, as a dihydrochloride, 339.27 and, in basic form, 266.34. The molecule has two pKa values (4.32 and 8.95) and the pH value of an aqueous solution (5 mg/ml) is 3; this aqueous solution is stable at room temperature. PHARMACOLOGY Effects on the Hypoxic Cell and on the Ischemic TissueIschemia is defined as a deficiency of blood supply in a given tissue, and consequently of oxygen supply to the cells. Ischemia results in a decrease of oxidative metabolism that is responsible for the various functional disorders observed in the cell: reduction in the production of energetic compounds, accumulation of protons, and increase in the generation of oxygen-derived free radicals. The aggression of oxygenderived free radicals towards living tissues is therefore superimposed on the energy disorders and added to the effects of acidosis, which severely alters cellular homeostasis and results in accumulation of calcium within the cell. This considerable excess of intracellular calcium blocks all vital enzymatic functions, leading to necrosis.Despite hypoxia or induced ischemia, trimetazidine maintains homeostasis and cellular functions and inhibits cytolysis. This activity has been evidenced in vivo, by Camilleri and Joseph (3), Fitoussi et al. (4), and Catroux et al. ( 5 ) , using different models of ischemia. After induction of left ventricular infarction in the rat by coro-

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Section: Pharm Acokineticsmentioning

confidence: 99%

Trimetazidine, A Cellular Anti‐ischemic Agent

Harpey

Clauser

Labrid

et al. 1988

Cardiovascular Drug Reviews

109

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“…Although being considered a well-tolerated drug, [5] an increasing number of case reports concerning drug-induced parkinsonism, gait disorder, and tremor caused by trimetazidine have been published, [6][7][8] resulting in a recommendation for a careful cost-benefit assessment of the drug. In the course of drug development and follow-up studies, analytical approaches for trimetazidine have been developed based on thin-layer chromatography, [9] liquid chromatography with fluorescence detection, [10] gas chromatography-mass spectrometry (GC-MS), [11] and more recently liquid chromatography-(tandem) mass spectrometry (LC-MS/MS), [12][13][14][15][16][17] one of which focusing particularly on the characterization of trimetazidine metabolites in human plasma and urine. [18] Since January 2014, trimetazidine belongs to the list of prohibited substances established by the World Anti-Doping Agency (WADA) [19] and a first adverse analytical finding was recently reported during the XXII.…”

Section: Introductionmentioning

confidence: 99%

Doping control analysis of trimetazidine and characterization of major metabolites using mass spectrometric approaches

Sigmund

Koch

Orlovius

et al. 2014

Drug Testing and Analysis

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Since January 2014, the anti-anginal drug trimetazidine [1-(2,3,4-trimethoxybenzyl)-piperazine] has been classified as prohibited substance by the World Anti-Doping Agency (WADA), necessitating specific and robust detection methods in sports drug testing laboratories. In the present study, the implementation of the intact therapeutic agent into two different initial testing procedures based on gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) is reported, along with the characterization of urinary metabolites by electrospray ionization-high resolution/high accuracy (tandem) mass spectrometry. For GC-MS analyses, urine samples were subjected to liquid-liquid extraction sample preparation, while LC-MS/MS analyses were conducted by established 'dilute-and-inject' approaches. Both screening methods were validated for trimetazidine concerning specificity, limits of detection (0.5-50 ng/mL), intra-day and inter-day imprecision (<20%), and recovery (41%) in case of the GC-MS-based method. In addition, major metabolites such as the desmethylated trimetazidine and the corresponding sulfoconjugate, oxo-trimetazidine, and trimetazidine-N-oxide as identified in doping control samples were used to complement the LC-MS/MS-based assay, although intact trimetazidine was found at highest abundance of the relevant trimetazidine-related analytes in all tested sports drug testing samples. Retrospective data mining regarding doping control analyses conducted between 1999 and 2013 at the Cologne Doping Control Laboratory concerning trimetazidine revealed a considerable prevalence of the drug particularly in endurance and strength sports accounting for up to 39 findings per year.

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“…methyl] piperazine dihydrochloride regulates ionic and extracellular exchanges, correcting the abnormal flow of ions across the cell membrane caused by ischaemia and preventing cellular oedema caused by anoxia [24]. Few methods for the estimation of trimetazidine in biological .fluids were reported, TLC [25], HPLC with fluorescence [26] or electrochemical detection [27] and GC-MC 1281. Trimetazidine is also determined in tablets using HPTLC [29].…”

Section: Trimetazidine Hydrochloride (Tmh) I -[(234-trimethoxyphenyl)mentioning

confidence: 99%

Spectrophotometric determination of some pharmaceutical piperazine derivatives by charge-transfer and ion-pair complexation methods

et al. 2002

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Simple and sensitive spectropliotometric methods are described for the assay of three piperazine derivatives ketoconazole, trimetazidine hydrochloride and piribedil based on cliarge-transfer and ion-pair complexation reactions. The first method is based on the reaction of the basic drug with iodine as o-acceptor in dry 1,2-dichloroethane to form a yellow colour due to the formation of charge-transfer complex showing maximum absorbence at 363, 364 and 359 nm for ketoconazole, trimetazidine hydrochlorid and piribedil, respectively. The second method is based on the reaction of basic drug with bromocresol green (BCG) in dry 1,2- dichloroethane to form a stable yellow coloured complex with maximum absorbance at 407, 408 and 410 nm for ketoconazol, trimetazidine hydrochloride and piribedil, respectively. Beer's law was obeyed for both methods and the relative standard deviations were found to be less than 1%. The two methods can be applied for the analysis of tablets and cream, with no evidence of interference from excipients. A more detailed investigation of the complex was made with respect to its composition association constant and free energy cliange.

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Trimetazidine in Blood, Bile, Organs and Urine

Cited by 14 publications

References 1 publication

Trimetazidine, A Cellular Anti‐ischemic Agent

Trimetazidine, A Cellular Anti‐ischemic Agent

Doping control analysis of trimetazidine and characterization of major metabolites using mass spectrometric approaches

Spectrophotometric determination of some pharmaceutical piperazine derivatives by charge-transfer and ion-pair complexation methods

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