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Pharmacokinetics have been studied in healthy subjects using intravenous and oral administration of meldonium.

Absorption

After oral administration of single doses of 25, 50, 100, 200, 400, 800 or 1500 mg, the maximum plasma concentration of meldonium (Cmax) and the area under the concentration-time curve (AUC) increased in proportion to the dose administered. The time to reach the maximum plasma concentration (tmax) is 1-2 hours. With repeated dosing, equilibrium plasma concentrations are reached within 72-96 hours after the first dose. Accumulation of meldonium in the blood plasma is possible. Dietary intake delays the absorption of meldonium without affecting the Cmax and AUC values.

Availabilty

Meldonium is rapidly distributed from the bloodstream to the tissues. Binding to plasma proteins increases with time after dosing. Meldonium and its metabolites partially cross the placental barrier.

Animal studies have shown that meldonium is excreted in breast milk.

Biotransformation

Metabolism studies in experimental animals have shown that meldonium is mainly metabolised in the liver.

Elimination

Renal excretion plays an important role in the elimination of meldonium and its metabolites. The elimination half-life (t1/2) of meldonium is approximately 4 hours. The elimination half-life varies with repeated dosing.

Acute toxicity

Meldonium is low toxic. The LD50 in mice and rats when administered orally is greater than 18 000 mg/kg.

Chronic toxicity

Repeated administration of meldonium to rats over six months did not cause adverse effects on body weight, blood composition, blood and urine biochemical parameters. Meldonium at doses of 20, 100 and 500 mg/kg per os had no effect on haematopoiesis, liver and kidney function and did not induce changes in visceral structure.

Carcinogenicity, mutagenicity

The drug has no mutagenic or carcinogenic properties.

Reproductive toxicity

No teratogenic or embryotoxic effects have been observed with meldonium in specific toxicity studies.

In reproduction studies in adult experimental animals, no effects related to meldonium administration on the number of corpora lutea, estrous cycle, mating and fertilisation rates were observed. From the results of the studies, the dose of meldonium which does not cause general toxic effects is 400 mg/kg/day and the dose which does not cause adverse effects on r e p r o d u c t i o n is 1600 mg/kg. In contrast, no toxic effects on foetal development were observed at doses above 1600 mg/kg/day

Meldonium is the structural analogue of the carnitine precursor gamma-butyrobetaine (GBB), in which

one of the carbon atoms is replaced by a nitrogen atom. Its effects on the body can be explained in two ways.

Effects on carnitine biosynthesis

Meldonium reversibly inhibits gamma-butyrobetaine hydroxylase, decreases carnitine biosynthesis and thus interferes with the transport of long-chain fatty acids across cell membranes, thus preventing the accumulation of activated forms of non-oxidised fatty acids, a potent deterrent. This prevents damage to cell membranes.

Decreasing carnitine concentrations under ischaemic conditions inhibit β-oxidation of fatty acids and optimise cellular oxygen consumption, stimulate glucose oxidation and restore ATP transport from its biosynthetic sites (mitochondria) to its consumption sites (cytosol). Essentially, the cells are supplied with nutrients and oxygen and their utilisation is optimised.

In turn, increased biosynthesis of carnitine’s precursor, GBB, activates NO-synthase, resulting in improved blood rheology and reduced peripheral vascular resistance.

As meldonium concentrations decrease, carnitine biosynthesis increases again and fatty acids are gradually restored to the cells.

The effectiveness of meldonium is thought to be based on increasing cellular tolerance to stress

(through changes in fatty acid levels).

Mediator function in a hypothetical GBB-ergic system

It is hypothesised that a neural signal transduction system, the GBB-ergic system, exists in the body, w h i c h allows the transmission of nerve impulses between somatic cells. The mediator of this system is the ester of the last precursor of carnitine, GBB. As a result of the action of GBB-esterase, the mediator returns an electron to the cell, thereby transferring an electrical impulse, but itself is converted into GBB. The hydrolysed form of GBB is then actively transported to the liver, kidneys and testes, where it is transformed into carnitine. Somatic cells synthesise new GBB molecules in response to the stimulus, allowing the signal to propagate.

As carnitine concentrations decrease, GBB synthesis is stimulated, resulting in an increase in GBB ester concentrations.

Meldonium, as noted above, is the structural analogue of GBB and is able to act as a “mediator”. In contrast, GBB-hydroxylase does not ‘recognise’ meldonium, so that carnitine concentrations decrease rather than increase. Thus, meldonium, both by replacing the ‘mediator’ itself and by contributing to the increase in GBB concentration, promotes the development of the body’s response. As a result, overall metabolic activity in other systems, such as the central nervous system (CNS), also increases.