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Pharmacology: Pharmacodynamics: 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 detoxificatlon. 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.
Pharmacokinetics: Absorption: Following oral administration of ademetionine, peak plasma concentrations are achieved 3-5 hrs 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 0.5-1 mg/L achieved 3-5 hrs after single doses ranging from 400-1000 mg. Plasma concentrations decline to baseline within 24 hrs.
Distribution: Volumes of distribution of 0.41 L/kg and 0.44 L/kg have been reported for doses of 100 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 1st 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: Excretion of unmetabollzed ademetionine in humans is split between urinary excretion (15.5±1.5 %) and fecal excretion (23.5±3.5 %).
Toxicology: Preclinical Safety Data: Toxicological studies were performed in multiple animal species (rat, mouse, dog) of both sexes. Chronic toxicity testing did not identify any significant changes to body organs. Single-dose toxicity, repeated-dose toxicity, reproduction toxicity and mutagenicity studies were performed and did not demonstrate any signs of toxic effects.
When administered throughout pregnancy, no adverse effects were observed in the growth and development of the embryo or fetus.
