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Ramelteon is a melatonin receptor agonist. According to the manufacturer, its molecular structure is composed of a substituted tetrahydroindenofuran derivative containing a propionamide moiety with one chiral center, and the compound is produced as the (S) enantiomer. It is freely soluble in organic solvents and is considered very slightly soluble in water or aqueous buffers with a pH between 3 and 11.

Ramelteon is available as a round, pale orange-yellow, film-coated 8-mg tablet. It should be stored between 15o and 30o C (59o and 86o F) and protected from moisture and humidity to avoid degradation of the contents.
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Normally, the pineal gland secretes melatonin at night to initiate sleep onset and to sustain night-time sleep. This action occurs because of melatonin’s inhibition of the neuronal firing rate that maintains wakefulness involved in the circadian rhythm of humans.

As a melatonin agonist, ramelteon mimics the actions of melatonin to trigger sleep onset. It weakly binds to the melatonin-3 receptor (MT3 ) and has high selectivity as an agonist for MT1 and MT2 receptors in the suprachiasmic nucleus. Its high affinity for MT1 and MT2 is thought to exert its sleep-promoting properties in a fashion similar to how endogenous melatonin acts in maintaining a normal sleep-wake cycle. The MT1 receptor is believed to regulate sleepiness, whereas the MT2 receptor is probably involved in the adjustment of circa-dian rhythms.

The binding affinity of ramelteon to these receptors is three to 16 times that of melatonin. This property is thought to exert an increased potency when compared with that of melatonin. However, no comparison study has been performed to determine whether the recommended dose of ramelteon (8 mg) exerts any advantage over standard doses of melatonin (0.3 mg), including long-term usage.


Absorption and Distribution

Ramelteon is rapidly absorbed after oral administration. Administration of ramelteon after a high-fat meal results in a 31% increase in the area-under-the-curve (AUC) concentration and in a 22% decrease in peak concentration (Cmax). The median time of maximum concentration (Tmax) is delayed by 45 minutes after administration with food (Table 1).

The Cmax is approximately 0.5 to 1.5 hours after fasting with oral administration. The drug has extensive first-pass metabolism, with an absolute oral bio­availability of 1.8%. Plasma protein-binding ability is moderate at 82% in human serum, with the majority of binding to serum albumin accounting for 70%. Thus, the drug is not highly protein-bound. No drug-drug interactions caused by this mechanism have been reported.
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The mean volume of distribution of ramelteon after intravenous (IV) administration is 73.6 liters, which suggests substantial distribution to the tissues.

Metabolism and Elimination

Ramelteon is metabolized primarily via the hepatic system. It is oxidized to hydroxyl and carbonyl derivatives, with secondary metabolism producing glu-curonide conjugates. Cytochrome CYP 1A2 is the major isoenzyme involved; the CYP 2C9 and CYP 3A4 isoenzymes have a minor role.

Ramelteon has an active major metabolite, M-II. M-II has a much lower binding affinity than the parent molecule for MT1 and MT2 receptors. Thus, it is much less potent than the parent drug, but it circulates at higher concentrations to exhibit a greater systemic exposure than the parent molecule. It also has weak affinity for the serotonin receptor 5-HT2B. No other appreciable affinities for other receptors or endogenous enzymes have been observed.

After oral administration, 84% of the drug is excreted in the urine and 4% is eliminated in the feces. Less than 0.1% is excreted as the parent compound.

The elimination half-life of the parent drug is approximately 1 to 2.6 hours, a relatively short duration. The active metabolite’s elimination half-life is slightly longer, at two to five hours.