Pharmacology of agomelatine Agomelatine is a melatonin (MT) analogue with agonistic properties. It binds to MT1 und MT2 receptors with similar affinity as melatonin. Moreover, it antagonises serotonin 5-HT2C receptors whereas the neuronal uptake of monoamines is not affected. The drug does not bind to receptors for histamine, acetylcholine, dopamine, noradrenaline or adrenaline. Microdialysis studies in rodents have shown that agomelatine enhances the release of dopamine and noradrenaline in the prefrontal cortex. In animal models with altered circadian rhythm agomelatine has a normalizing effect. In animal models of depression (e. g. learned helplessness, chronic mild stress or social stress) agomelatine exhibits antidepressant potency which was confirmed in clinical studies. Agomelatine is well absorbed (>80%), its bioavailability, however, is limited to only 3% due to marked first pass metabolism. Maximal blood levels are attained within 1 to 2 hours. The elimination half life is 1 to 2 hours. Following oral administration, agomelatine is primarily metabolised by the hepatic cytochrome P450 (CYP) isoenzyme CYP1A2 (90%). CYP2C9 and CYP2C19 are of minor importance (10%). The metabolites do not contribute to the pharmacological action. The serotonin selective antidepressant fluvoxamine, which is a potent inhibitor of CYP1A2 and CYP2C9, markedly inhibits agomelatine clearance. Therefore, fluvoxamine or other inhibitors of CYP1A2 should not be combined with agomelatine. Smoking enhances the clearance of agomelatine, but dose adaptation is not necessary for smokers. Age and renal impairment do not affect the pharmacokinetics of agomelatine. Due to its pharmacological profile, agomelatine is a safe and novel approach to treat depression.
