Ademetionine

S-adenosyl-L-methionine (ademetionine) is a naturally occurring amino acid present in virtually all body tissues and fluids. Ademetionine functions primarily as a co-enzyme 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.

Absorption

In humans, following intravenous administration, the ademetionine pharmacokinetic profile is bi-exponential and composed of a rapid apparent distribution phase into the tissues and a terminal elimination phase characterized by a half-life of approximately 1.5 hours. When administered intramuscularly, absorption of ademetionine is practically complete (96%); the maximum plasma concentrations of ademetionine are reached after approximately 45 minutes. Following oral administration of ademetionine, peak plasma concentrations are achieved 3 to 5 hours after ingestion of enteric-coated tablets (400–1000 mg). Oral bioavailability is enhanced when ademetionine is administered under fasting conditions. 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.

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, ademetioninedependent 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 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.