Chemical formula: C₁₄H₂₂N₂O₃ Molecular mass: 266.341 g/mol PubChem compound: 21109
By preserving energy metabolism in cells exposed to hypoxia or ischaemia, trimetazidine prevents a decrease in intracellular ATP levels, thereby ensuring the proper functioning of ionic pumps and transmembrane sodium-potassium flow whilst maintaining cellular homeostasis.
Trimetazidine inhibits β-oxidation of fatty acids by blocking long-chain 3-ketoacyl-CoA thiolase, which enhances glucose oxidation. In an ischaemic cell, energy obtained during glucose oxidation requires less oxygen consumption than in the β-oxidation process. Potentiation of glucose oxidation optimizes cellular energy processes, thereby maintaining proper energy metabolism during ischaemia.
In patients with ischaemic heart disease, trimetazidine acts as a metabolic agent, preserving the myocardial high-energy phosphate intracellular levels. Anti-ischemic effects are achieved without concomitant haemodynamic effects.
Trimetazidine after oral administration and absorption from the digestive tract reaches the maximum concentration in the serum after about 5 hours from administration of the drug. Over 24 hours the plasma concentration remains at levels above or equal to 75% of the maximum concentration for 11 hours. The steady concentration of the drug in the serum is reached after 60 hours and is stable throughout the period of treatment. No interactions with foodstuffs have been found.
The pharmacokinetic characteristics of trimetazidine prolonged-release tablets are not influenced by meals.
The drug binds to plasma proteins at about 16%. The volume of distribution is 4.8 l/kg, which means good penetration of the drug into the tissues.
Trimetazidine is eliminated mainly in the urine, in unchanged form. The average half-life is 7 hours, in patients over age 65 years it increases to 12 hours.
Total clearance of trimetazidine is the result of major renal clearance which is directly correlated to creatinine clearance and, to a lesser extent, to liver clearance which is reduced with age.
A specific clinical study carried out in an elderly population using a dosage of 2 tablets per day taken in 2 doses, analysed by a kinetic population method, showed an increase in plasma exposure which does not justify a dosage modification.
No pharmacokinetic data are available for the use of trimetazidine in hepatically impaired patients.
The acute toxicity of trimetazidine in mice, rats and guinea pigs is low. Repeated-dose toxicity studies with trimetazidine have been performed in rats and in dogs and no toxicological target organ was identified in these studies. Trimetazidine was not genotoxic in a standard battery of in vitro and in vivo tests. Reproductive toxicity studies were performed with trimetazidine in rats, mice and rabbits, and no adverse effects of trimetazidine on reproductive function (especially no teratogenic effects) were observed. In embryotoxicity studies in rats and rabbits, trimetazidine did not show any teratogenic effects. No modifications of reproductive functions were observed in a three generation study performed in rats. No conventional studies on fertility or pre/postnatal development were performed.
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