Transmetil Mechanism of Action

Pharmacotherapeutic group: Amino acids and derivatives. ATC-Code: A16AA02.
Pharmacology: Pharmacodynamics: Ademetionine or S-adenosyl-L-methionine, is a derivative of the amino acid methionine. Because of structural instability, stable salt forms of ademetionine are required for its use as an oral drug. The active ingredient is the salt, ademetionine 1,4-butanedisulfonate (ademetionine SD4).
Mechanism of action and Pharmacodynamics effects: S-adenosyl-L-methionine (ademetionine) is a naturally occurring amino acid present in virtually all body tissues and fluids. Ademetionine functions primarily as a coenzyme and donor transfer of the methyl group (transmethylation) is an essential metabolic process in humans and animals. Methyl transfer is also essential to the development of the phospholipid bilayer of cell membranes and contributes to membrane fluidity. Ademetionine can penetrate the blood-brain barrier and ademetionine-mediated transmethylation is critical in the formation of neurotransmitters in the central nervous system including catecholamines (dopamine, noradrenalin, adrenaline), serotonin, melatonin and histamine.
Ademetionine is also a precursor in the formation of physiological sulfurated compounds (cysteine, taurine, glutathione, CoA, etc.) via transsulfuration. Glutathione, the most potent antioxidant in the liver, is important in hepatic detoxification. Ademetionine increases hepatic glutathione levels in alcoholic and non-alcoholic liver disease patients.
Both folate and vitamin B₁₂ are essential co-nutrients in the metabolism and replenishment of ademetionine.
Clinical efficacy: Intrahepatic cholestasis: The experience accumulated with the oral and parenteral use of ademetionine for more than 20 years has shown that this drug is effective in the treatment of intrahepatic cholestasis of liver disease and of pregnancy and other chronic liver disorders.
Intrahepatic cholestasis is a complication of chronic liver diseases and other causes of hepatocellular damage. In hepatic disease, normal hepatocyte function such as the regulation and clearance of bile acids is compromised, resulting in cholestasis.
The use of ademetionine has been studied in patients with chronic liver diseases that involve intrahepatic cholestasis, including primary biliary cirrhosis, drug-induced liver injury, viral hepatitis, cholestasis induced by total parenteral nutrition, alcoholic liver disease and non-alcoholic fatty liver disease.
More than 2,700 patients affected by intrahepatic cholestasis and/or chronic liver diseases have been included into the clinical trials with ademetionine and approximately 2000 were treated with this drug. In most of these trials, ademetionine was compared with placebo due to the almost total absence of alternative therapies at the point in time. In almost 90% of cases a cholestatic component was associated with chronic liver diseases. The remaining patients were suffering from alcoholic liver disease, acute and chronic hepatitis or intrahepatic cholestasis of pregnancy. The efficacy parameters considered in the clinical studies included the main subjective symptoms of cholestasis (itching, jaundice, fatigue, return to well-being), and biochemical markers of cholestasis and liver damage, such as total and conjugated bilirubin, alkaline phosphatase, bile salts, transaminases, γ-glutamyltransferase. The treatment with ademetionine given IV, IM or orally, improved intrahepatic cholestasis due to chronic liver disease or pregnancy, and alcoholic cirrhosis. The effects of IV or IM treatment are evident after 1 - 2 weeks of therapy, whereas, oral treatment is suitable for maintenance therapy.
One long-term, double-blind, placebo controlled study of 123 men and women with alcoholic liver cirrhosis found that 1,200 mg/day ademetionine for 2 years may improve survival rates and delay the need for liver transplants more effectively than placebo. The overall mortality/liver transplantation at the end of the trial decreased from 30% in the placebo group to 16% in the ademetionine group, although the difference was not statistically significant. Long-term treatment with ademetionine reduced the overall mortality/liver transplantation, especially in patients with less advanced liver disease.
Relief of fatigue in chronic liver disease (CLD): A number of studies have demonstrated the efficacy of Ademetionine in the treatment of fatigue in patients with CLD. Ademetionine has shown an improvement of fatigue in CLD consistently over several studies. An integrated analysis of subjects with fatigue at baseline showed the effect of ademetionine treatment on fatigue response along with a range of other symptoms i.e., depression, jaundice, malaise and pruritus. In subjects with ALD, treatment with ademetionine significantly improved depressed mood in individuals who also responded in terms of fatigue.
Moreover, in subjects with ALD or with NALD, treatment with ademetionine significantly improved jaundice, malaise and pruritus in individuals who also responded in terms of fatigue.
Intrahepatic cholestasis of pregnancy: The efficacy of treatment with Ademetionine was assessed in 7 clinical trials including 264 women with intrahepatic cholestasis of pregnancy. Of these, 156 were treated with ademetionine, 21 received placebo, 60 an active control (ursodeoxycholic acid) and 27 ademetionine plus ursodeoxycholic acid. The treatment with ademetionine given IV, IM or orally, was effective in treatment of intrahepatic cholestasis of pregnancy with improvement of pruritus and biochemical parameters.
A review of the clinical efficacy of ademetionine for the treatment of depression, and liver disease was published in 2002 by the Agency for Healthcare Research and Quality (AHRQ,USA). The meta-analysis of these studies concludes that ademetionine is more effective than placebo for relief of symptoms of depression, pruritus in cholestasis of pregnancy, and intrahepatic cholestasis. Ademetionine is more effective than placebo in reducing serum bilirubin for cholestasis of pregnancy and for intrahepatic cholestasis. Treatment with ademetionine was equivalent to standard therapy for depression.
Prevention and Treatment of Drug-induced liver injury (DILI): Clinical data show that ademetionine is effective in both the prevention and treatment of DILI of various causes (e.g. antivirals, immunosuppressants, anti-cancer therapy). The demonstrated protective effects of ademetionine may be attributable to its active involvement in liver detoxification processes.
Depression: Ademetionine has been given orally or parenterally in the management of depression. The results from several review articles on the efficacy of ademetionine in the treatment of depressive disorders and from the metaanalysis of the clinical studies show that ademetionine, at doses of 200 - 1600 mg/day, possesses a pronounced anti-depressive activity in patients suffering from different types of depression (uni polar endogenous, neurotic, dysthymic disturbances). Several double-blind studies have found the efficacy of ademetionine in treating depressive disorders superior to placebo and similar to tricyclic antidepressants. The anti-depressive action is rapid and manifests itself within 5 - 7 days of treatment in the absence of, anti-cholinergic reactions.
Pharmacokinetics: Absorption: Following oral administration of ademetionine, peak plasma concentrations obtained after administration of enteric-coated tablets are dose related, with peak plasma concentrations of 0.5 to 1 mg/l achieved 3 to 5 hours after single doses ranging from 400 mg to 1000 mg. Plasma concentrations decline to baseline within 24 hours. Oral bioavailability is enhanced when ademetionine is administered under fasting conditions. Following oral administration of ademetionine, peak plasma concentrations obtained after administration of enteric-coated tablets are dose related, with peak plasma concentrations of 0.5 to 1 mg/L achieved 3 to 5 hours after single doses ranging from 400 mg to 1000 mg. Plasma concentrations decline to baseline within 24 hours. Oral bioavailability is enhanced when ademetionine is administered under fasting conditions.
Distribution: Volumes of distribution of 0.41 and 0.44 l/kg have been reported for doses of 100 mg and 500 mg ademetionine, respectively. Binding to plasma proteins is negligible being ≤ 5%.
Metabolism: The reactions that produce, consume, and regenerate ademetionine are called the ademetionine cycle. In the first step of this cycle, ademetionine-dependent methylases use ademetionine as a substrate and produce S-adenosyl-homocysteine. S-adenosyl-homocysteine is then hydrolyzed to homocysteine and adenosine by S-adenosyl- homocysteine hydrolase. The homocysteine is then recycled back to methionine with the transfer of a methyl group from 5-methyltetrahydrofolate. Finally, methionine can be converted back to ademetionine, completing the cycle.
Excretion: In tracer balance studies using orally administered, radioactive (methyl 14C) SAMe in normal volunteers, urinary excretion of radioactivity was 15.5 ± 1.5% after 48 hours and fecal excretion was 23.5 ± 3.5% after 72 hours, leaving approximately 60% incorporated into stable pools.
Toxicology: Preclinical Safety Data: Toxicology studies were performed as single dose and repeat dose in multiple animal species including mouse, rat, hamster and dog of both sexes by the oral, subcutaneous, intravenous, and intramuscular route.
Repeat dose toxicity testing indicated that the kidney is the target organ in the rat and hamster and to a much lesser extent in the dog. Possibly, the testis is a further target organ in the rat. No other significant changes to body organs were observed. Single dose toxicity, repeated dose toxicity through 104 weeks, reproduction toxicity, and mutagenicity studies did not demonstrate any other notable signs of toxic effects.