Heptral, lyophilizate 400 mg 5 pcs

Pharmacotherapeutic group: Other drugs for the gastrointestinal tract and metabolism, amino acids and their derivatives

ATC code: A16AA02

Pharmacological properties

Pharmacodynamics

Ademetionine belongs to the group of hepatoprotectors, also has antidepressant activity. It has choleretic and cholokinetic effect, has detoxifying, regenerating, antioxidant, antifibrotic and neuroprotective properties.

It replenishes the S-adenosyl-L-methionine (ademetionine) deficiency and stimulates its production in the body, contained in all body fluids. The highest concentration of ademetionine is found in the liver and brain. Ademetionine plays a key role in the metabolic processes of the body and takes part in major biochemical reactions: transmethylation, transsulfurization and transamination.

In transmethylation reactions ademetionine donates methyl groups for the synthesis of cell membrane phospholipids, neurotransmitters, nucleic acids, proteins, hormones and others. In transsulfurization reactions ademetionine is a precursor of cysteine, taurine, glutathione (providing redox mechanism of cellular detoxification), coenzyme A (is included into biochemical reactions of tricarboxylic acid cycle and fills the cell energy potential).

Increases glutamine content in the liver, plasma cysteine and taurine, decreases methionine content in the serum, normalizing metabolic reactions in the liver. After decarboxylation it participates in aminopropylation reactions, as precursor of polyamines – putrescine (stimulator of cell regeneration and hepatocyte proliferation), spermidine and spermine, which are part of the ribosome structure, which reduces the risk of fibrosis. It has a choleretic effect. Ademetionine normalizes the synthesis of endogenous phosphatidylcholine in hepatocytes, which increases membrane fluidity and polarization. This improves the function of bile acid transport systems associated with membranes of hepatocytes and contributes to bile acid passage to biliary tracts.

Effective with intradolocular variant of cholestasis (disorders of bile synthesis and flow). Ademetionine reduces the toxicity of bile acids in the hepatocyte by performing their conjugation and sulfation. Conjugation with taurine increases solubility of bile acids and their excretion from the hepatocyte. The process of sulfation of bile acids allows their elimination by kidneys and facilitates passing through hepatocyte membrane and excretion with bile.

In addition, sulfated bile acids additionally protect liver cell membranes from toxic effects of nonsulfated bile acids (in high concentrations present in hepatocytes with intrahepatic cholestasis). In patients with diffuse liver diseases (cirrhosis, hepatitis) with intrahepatic cholestasis syndrome, ademetionine reduces the severity of skin itching and changes in biochemical parameters, including direct bilirubin concentration, alkaline phosphatase activity, aminotransferases and others. Choleretic and hepatoprotective effect persists up to 3 months after discontinuation of treatment. It is shown to be effective in hepatopathies caused by various hepatotoxic drugs. Antidepressant activity appears gradually from the end of the first week of treatment and stabilizes during 2 weeks of treatment.

Several studies have confirmed the effectiveness of ademetionine in treatment of increased fatigability in patients with chronic liver disease. A pooled analysis of data from patients with pre-treatment symptoms of fatigue proved the effect of ademetionine treatment in reducing symptoms of fatigue in combination with a number of other symptoms, such as depression, hiccuria of the skin and mucous membranes, malaise and skin itching. Ademetionine treatment significantly improved mood in patients with alcoholic liver disease, who simultaneously achieved a positive response from symptoms of increased fatigability. In addition, in patients with alcoholic liver disease and nonalcoholic fatty liver disease with achieved response to ademetionine treatment on the side of symptoms of increased fatigability there was also observed a significant relief of such symptoms as hirsuteness of skin and mucous membranes, malaise and skin itching.

Pharmacokinetics

Tablets are covered with a film coating that dissolves only in the intestine, so that ademetionine is released in the duodenum.

Absorption

Bioavailability when ingested is 5%; it is increased when taken on an empty stomach. Maximal concentrations (Cmax) of ademetionine in plasma are dose-dependent – 0.5-1 mg/l 3-5 hours after a single oral dose from 400 to 1000 mg. Cmax of ademetionine in plasma decrease to the initial level within 24 hours.

Distribution

Binding with blood plasma proteins is insignificant – 5%.
It penetrates through the blood-brain barrier. There is a significant increase in concentration of ademetionine in cerebrospinal fluid.

Metabolism

Metabolized in the liver. The process of ademetionine formation, expenditure and reformation is called the ademetionine cycle. In the first step of this cycle, ademetionine-dependent methylases use ademetionine as a substrate to produce S-adenosylhomocysteine, which is then hydrolyzed to homocysteine and adenosine by S-adenosylhomocysteine hydralase. Homocysteine, in turn, undergoes a reverse transformation to methionine by transferring the methyl group from 5-methyltetrahydrofolate. Eventually, methionine can be converted to ademethionine, completing the cycle.

Excretion

The half-life (T½) is 1.5 h. It is excreted by the kidneys. In studies in healthy volunteers, when ingested with labeled (methyl 14C) S-adenosyl-L-methionine, 15.5% ± 1.5% radioactivity was detected in the urine after 48 hours, and 23.5% ± 3.5% radioactivity in the feces after 72 hours. Thus, about 60% was deposited.

Indications

Active ingredient

Composition

How to take, the dosage

Interaction

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Contraindications

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