Study to investigate the absolute bioavailability of a single oral dose of ramelteon (TAK-375) in healthy male subjects

Stevenson, Stuart S.; Bryson, S. M.; Amakye, Dereck D.; Hibberd, Mark G.

doi:10.1016/j.clpt.2003.11.085

Cited by 21 publications

(22 citation statements)

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“…Ramelteon (12) is mostly administered at an oral dose of 8 mg, or 4 mg in elderly subjects, and is rapidly absorbed by the gastrointestinal tract, with an absorption rate, under fasting conditions, of about 84%. However, the total bioavailability frequently remained in the range of 1.8%, with a high variability between 0.5 and 12% [294]. After a dose of 8 mg, the peak plasma concentration of up to 57 ng/mL is reached in about 45 min, with an interindividual variability ranging from 30 min to 1.5 h. The half-life of circulating ramelteon (12) is in the range of 1-2 h [295,296] and, thus, longer than that of melatonin (1).…”

Section: Synthetic Melatonin Receptor Agonistsmentioning

confidence: 97%

Melatonin and Synthetic Melatonergic Agonists: Actions and Metabolism in the Central Nervous System

Hardeland¹,

Pöeggeler²

2012

CNSAMC

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The CNS is both source and target of melatonin. This methoxyindole formed in the pineal gland is also produced in other CNS regions and additionally enters the brain by uptake from the circulation as well as via the pineal recess. The mammalian circadian pacemaker, the suprachiasmatic nucleus (SCN), not only controls the pineal, but also receives a feedback information on darkness. Two G protein-coupled melatonin receptors, MT1 and MT2, are responsible for the transduction of many melatonergic actions. High receptor densities are especially found in the SCN, but their presence at lower expression levels in other areas is functionally important. Various metabolites and analogs are formed in the CNS, such as N-acetylserotonin, 5-methoxytryptamine, 5-methoxytryptophol, 5-methoxylated kynuramines, and even 6-sulfatoxymelatonin. The chronobiological effects of melatonin go beyond the resetting of a single circadian oscillator. They contribute to phase relationships between oscillatory subsets and are required for robust rhythm amplitudes. CNS effects of melatonin comprise sleep initiation, antiexcitatory, antiepileptic, antinociceptive, anxiolytic, proneurotrophic, antiinflammatory, antioxidant and other neuroprotective actions. The role as a sleep-promoting compound, which is limited by its short half-life in the circulation, has led to the development of controlled-release formulations and of various synthetic agonists, such as ramelteon, agomelatine, tasimelteon, TIK-301, UCM765 and UCM924. Their differences concerning receptor affinities, preferences for receptor subtypes, and pharmacokinetics are discussed, as well as additional antidepressive actions of agomelatine and TIK-301 based on properties as antagonists of the serotonergic 5-HT2C receptor. Indirect antidepressive effects by melatonergic drugs are largely explained by circadian readjustments.

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Section: Synthetic Melatonin Receptor Agonistsmentioning

confidence: 97%

Melatonin and Synthetic Melatonergic Agonists: Actions and Metabolism in the Central Nervous System

Hardeland¹,

Pöeggeler²

2012

CNSAMC

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“…Cytochrome P450 (CYP)1A2 is the major hepatic enzyme involved in ramelteon metabolism. Four principal metabolites of ramelteon (M-I, -II, -III and -IV) have been identified [58]. Among these, M-II has been found to occur in much higher concentrations, with systemic concentration 20-100-fold greater than ramelteon.…”

Section: Pharmacokinetics Of Ramelteonmentioning

confidence: 98%

“…On oral administration, ramelteon is absorbed rapidly, with a T max of less than 1 h [58]. The absolute bioavailability of the oral formulation of ramelteon is less than 2% (range: 0.5-12%) [58].…”

Section: Pharmacokinetics Of Ramelteonmentioning

confidence: 99%

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Therapeutic potential of melatonin agonists

Cardinali¹,

Pandi-Perumal

Srinivasan

et al. 2008

Expert Review of Endocrinology & Metabolism

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Melatonin, a hormone secreted by the pineal gland, has been successfully employed to improve sleep in both normal patients and insomniacs, and for the treatment of circadian rhythm sleep disorders. Melatonergic MT 1 and MT 2 receptors exist in high concentrations in the suprachiasmatic nucleus of the hypothalamus and have been shown to be instrumental for the sleep-promoting and circadian rhythm-regulating effects of melatonin. A lack of consistency among reports on the therapeutic efficacy of melatonin has been attributed to differences in melatonin's bioavailability and the short half-life of the hormone. In view of the need for longer acting melatonergic agonists that improve sleep efficiency without causing drug abuse or dependency, ramelteon (Rozerem™, Takeda) was developed. Ramelteon, which acts via MT 1 /MT 2 melatonergic agonism, has been found clinically effective for improving total sleep time and sleep efficiency in insomniacs. Agomelatine (Valdoxan™, Servier) is another MT 1 /MT 2 melatonergic agonist that also displays antagonist activity at 5-HT 2C serotonin receptors. Agomelatine has been found effective in treating depression and sleep disorders in patients with major depressive disorder. A slow-release preparation of melatonin (Circadin™, Neurim) has been shown to be effective in treating sleep disorders in the elderly population.

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“…CYPA2 is the major hepatic enzyme involved in ramelteon metabolism. Four principal metabolites of ramelteon, namely M-I, M-II, M-III and M-IV have been identified [90]. Among the M-II occurs at a high concentration with its systemic level being 20 to 100-fold greater than ramelteon.…”

Section: Melatonergic Agonist Ramelteon For Treatment Of Admentioning

confidence: 99%

Alzheimer’s Disease: Focus on the Neuroprotective Role of Melatonin

Srinivasan¹

2012

J Neurol Res

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Alzheimer's disease (AD) is characterized by a progressive loss of memory and cognitive function, and by behavioural and sleep disturbances, including insomnia. The pathophysiology of AD has been attributed to oxidative stress-induced amyloid-β protein (Aβ) deposition. Abnormal tau protein, mitochondrial dysfunction and protein hyper-phosphorylation have been demonstrated in neural tissues of AD patients. AD patients exhibit severe sleep-wake disturbances and these sleep disturbances are associated with rapid cognitive decline and memory impairment. Optimally effective management of AD patients will likely require a drug that can arrest Aβ -induced neurotoxic effects and can also restore the disturbed sleep-wake rhythm, with improvement in sleep quality. In this context, the pineal hormone melatonin has been demonstrated to be an effective antioxidant that can prevent Aβ -induced neurotoxic effects through a variety of mechanisms. Sleep deprivation itself produces many effects including oxidative damage, impaired mitochondrial function, neurodegenerative inflammation, altered proteosomal processing and abnormal activation of enzymes. In addition to treating the signs and symptoms of AD, treatment of sleep disturbances may also be necessary for preventing and arresting AD progression. Besides melatonin, a number of melatonergic agonists such as ramelteon, agomelatine and tasimelteon are now used clinically for treating insomnia and other sleep disorders. Their use may also be beneficial in treating Alzheimer's disease.

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Study to investigate the absolute bioavailability of a single oral dose of ramelteon (TAK-375) in healthy male subjects

Cited by 21 publications

References 0 publications

Melatonin and Synthetic Melatonergic Agonists: Actions and Metabolism in the Central Nervous System

Melatonin and Synthetic Melatonergic Agonists: Actions and Metabolism in the Central Nervous System

Therapeutic potential of melatonin agonists

Alzheimer’s Disease: Focus on the Neuroprotective Role of Melatonin

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