Chemical formula: C₁₃H₁₆N₂O₂ Molecular mass: 232.278 g/mol PubChem compound: 896
The activity of melatonin at the MT1, MT2 and MT3 receptors is believed to contribute to its sleep-promoting properties, as these receptors (mainly MT1 and MT2) are involved in the regulation of circadian rhythms and sleep regulation.
Melatonin is a naturally occurring hormone produced by the pineal gland and is structurally related to serotonin. Physiologically, melatonin secretion increases soon after the onset of darkness, peaks at 2-4 am and diminishes during the second half of the night. Melatonin is associated with the control of circadian rhythms and entrainment to the light-dark cycle. It is also associated with a hypnotic effect and increased propensity for sleep.
Because of the role of melatonin in sleep and circadian rhythm regulation, and the age related decrease in endogenous melatonin production, melatonin may effectively improve sleep quality particularly in patients who are over 55 with primary insomnia.
In the paediatric population comprising 16 ASD children ages 7-15 years old suffering from insomnia, following melatonin 2 mg (2 × 1 mg mini-tablets) administration after a standardized breakfast, melatonin concentrations peaked within 2 hours after administration and remained elevated for 6 hours thereafter with a Cmax (SD) of 410 pg/ml (210) in the saliva.
In adults, following melatonin 5 mg (1 × 5 mg mini-tablet) administered after food, melatonin concentrations peaked within 3 hours after administration; Cmax (SD) was 3.57 ng/ml (3.64) in plasma. Under fasted conditions Cmax was lower (1.73 ng/ml) and tmax was earlier (within 2 hours) with a minor effect on AUC-∞ that was slightly reduced (-14%) as compared to fed state.
The absorption of orally ingested melatonin is complete in adults and may be decreased by up to 50% in the elderly. The kinetics of melatonin are linear over the range of 2-8 mg.
Data with 2 mg prolonged release melatonin tablets and data with 1 mg and 5 mg mini-tablets indicate that there is no accumulation of melatonin after repeated dosing. This finding is compatible with the short half-life of melatonin in humans.
Bioavailability is in the order of 15%. There is a significant first pass effect with an estimated first pass metabolism of 85%.
The in vitro plasma protein binding of melatonin is approximately 60%. Melatonin is mainly bound to albumin, alpha1-acid glycoprotein and high density lipoprotein.
Melatonin undergoes a fast first hepatic pass metabolism and is metabolised predominantly by CYP1A enzymes, and possibly CYP2C19 of the cytochrome P450 system with elimination half life of ca 40 minutes. Prepubertal children and young adults metabolize melatonin faster than adults. Altogether, melatonin metabolism declines with age, with pre-pubertal and pubertal metabolism faster than at older age. The principal metabolite is 6-sulfatoxy-melatonin (6-S-MT), which is inactive. The site of biotransformation is the liver. The excretion of the metabolite is completed within 12 hours after ingestion.
Melatonin does not induce CYP1A2 or CYP3A enzymes in vitro at supra-therapeutic concentrations.
Terminal half life (t½) is 3.5-4 hours. Two liver-mediated metabolic pathways account for around 90% of melatonin metabolism. The predominant metabolic flux is through hydroxylation at C6 via the hepatic microsome P-450 system to yield 6-hydroxymelatonin. The second, less significant, pathway is 5-demethylation to yield a physiological melatonin precursor, N-acetylserotonin. Both 6-hydroxymelatonin and N-acetylserotonin are ultimately conjugated to sulfate and glucoronic acid, and excreted in the urine as their corresponding 6-sulfatoxy and 6-glucoronide derivatives.
Elimination is by renal excretion of metabolites, 89% as sulfated and glucoronide conjugates of 6-hydroxymelatonin (over 80% as 6-sulfatoxy melatonin) and 2% is excreted as melatonin (unchanged active substance).
A 3-4-fold increase in Cmax is apparent for women compared to men. A five-fold variability in Cmax between different members of the same sex has also been observed. However, no pharmacodynamic differences between males and females were found despite differences in blood levels.
There is no experience of the use of melatonin in paediatric patients with renal impairment. However as melatonin is mainly eliminated via liver metabolism, and the metabolite 6-SMT is inactive, renal impairment is not expected to influence clearance of melatonin.
The liver is the primary site of melatonin metabolism and therefore, hepatic impairment results in higher endogenous melatonin levels.
Plasma melatonin levels in patients with cirrhosis were significantly increased during daylight hours. Patients had a significantly decreased total excretion of 6-sulfatoxymelatonin compared with controls. There is no experience of the use of melatonin in paediatric patients with liver impairment. Published data demonstrate markedly elevated endogenous melatonin levels during daytime hours due to decreased clearance in patients with hepatic impairment.
Non-clinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development.
A slight effect on post-natal growth and viability was found in rats only at very high doses, equivalent to approximately 2000 mg/day in humans.
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