Melatonergic Treatment: Focus on Metabolism and Chronobiology

Melatonin is produced in various organs, but its preferentially nocturnal synthesis and release by the pineal gland is decisive for its chronobiological actions. The short half-life of circulating melatonin has been reason for developing synthetic melatonergic agonists. With regard to age- and disease-related dysfunction of the melatonergic system, treatment with melatonin or its synthetic analogs may be used for alleviating health problems with a respective etiology. This review addresses limitations arising from drug-specific metabolism and disregarded chronobiological rules.
Metabolism: Differences are illustrated by comparing the metabolism of melatonin and two approved synthetic melatonergic agonists, ramelteon and agomelatine. Apart from hydroxylation and dealkylation reactions, melatonin can be converted to methoxylated kynuramines, a route absent in the two synthetic drugs. An unsual property is present in the ramelteon metabolite M-II, which still displays melatonergic activity, but attains 30 to100 times higher levels than the parent compound. Two double hydroxylated agomelatine metabolites may be involved in sometimes occurring hepatotoxicity.
Chronobiology of Melatonergic Drugs: Sleep latency facilitation and readjustment of circadian rhythms require only short actions. Circadian entrainment must consider the phase response curve and requires repetitive well-timed administration. Findings in nocturnally active rodents cannot be generally translated to humans, especially not regarding sleep and, perhaps, not in insulin resistance.
Melatonin and synthetic analogs can be suitable for treating sleep-onset difficulties, circadian rhythm sleep disorders and subtypes of depression with an etiology of circadian dysfunction. Applications in the field of metabolic syndrome and insulin resistance have to be seen with caution.