Ramelteon: Pharmacodynamics and Pharmacokinetics

Description

Ramelteon is indicated specifically for the treatment of insomnia characterized by difficulties with sleep onset. It helps you fall asleep faster so you can get a full night's rest.

Pharmacodynamics

Ramelteon is a melatonin receptor agonist with both high affinity for melatonin MT1 and MT2 receptors and selectivity over the non-human MT3 receptor. Ramelteon demonstrates full agonist activity in vitro in cells expressing human MT1 or MT2 receptors, and high selectivity for human MT1 and MT2 receptors compared to the non-human MT3 receptor.^[1] The affinity of ramelteon for the MT1 and MT2 receptors is 3 to 16 times higher than that of melatonin.^[2] Ramelteon has 8-fold higher affinity for the MT1 receptor over the MT2 receptor.The binding profile of ramelteon distinguishes it from melatonin, tasimelteon, and agomelatine. Remelteon has a clinically irrelevant affinity for the serotonin 5-HT1A receptor (Ki = 5.6 μM).

Pharmacokinetics

The total absorption of ramelteon is 84% while its oral bioavailability is 1.8%. The low bioavailability of ramelteon is due to extensive first-pass metabolism.

Ramelteon is metabolized in the liver primarily by oxidation via hydroxylation and carbonylation. It is also secondarily metabolized to produce glucuronide conjugates. Ramelteon is metabolized mainly by CYP1A2 while CYP2C enzymes and CYP3A4 are involved to a minor extent. The metabolites of ramelteon include M-I, M-II, M-III, and M-IV. Exposure to M-II is approximately 20- to 100-fold higher than to ramelteon.

Side effects

Side effects of ramelteon include somnolence, dizziness, fatigue, nausea, exacerbated insomnia, and changes in hormone levels. Ramelteon is an analogue of melatonin and is a selective agonist of the melatonin MT1 and MT2 receptors.

[1] Owen RT (April 2006). "Ramelteon: profile of a new sleep-promoting medication". Drugs of Today. 42 (4): 255–263. doi:10.1358/dot.2006.42.4.97084

[2] Atkin T, Comai S, Gobbi G (April 2018). "Drugs for Insomnia beyond Benzodiazepines: Pharmacology, Clinical Applications, and Discovery". Pharmacological Reviews. 70 (2): 197–245.doi:10.1124/pr.117.014381