Eszopiclone
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Eszopiclone
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| Systematic (IUPAC) name | |
| [(9S)-8-(5-chloropyridin-2-yl)-7-oxo-2,5,8- triazabicyclo[4.3.0]nona-1,3,5-trien-9-yl] 4-methylpiperazine-1-carboxylate |
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| Identifiers | |
| CAS number | |
| ATC code | N05 |
| PubChem | |
| DrugBank | |
| Chemical data | |
| Formula | C17H17ClN6O3 |
| Mol. mass | 388.808 g/mol |
| Pharmacokinetic data | |
| Bioavailability | ? |
| Protein binding | 52-59% |
| Metabolism | Hepatic oxidation and demethylation (CYP3A4 and CYP2E1-mediated) |
| Half life | 6 hours |
| Excretion | Renal |
| Therapeutic considerations | |
| Pregnancy cat. |
C (U.S.) |
| Legal status |
Schedule IV (U.S.) |
| Routes | Oral |
Eszopiclone, marketed by Sepracorand marco under the brand-name Lunesta®, is a nonbenzodiazepine hypnotic agent (viz., a sedative) used as a treatment for insomnia. Eszopiclone is the active stereoisomer of zopiclone, and belongs to the class of drugs known as cyclopyrrones. Its main selling point is that it does not lose its effectiveness with long-term use, unlike almost all other hypnotic sedatives, which are invariably prescribed for the relief of short-term (6-8 weeks) insomnia.
Eszopiclone may be less effective than traditional sleep-aids such as benzodiazepines, but it has several significant advantages. In addition to its suitability for long-term use, it lacks most of the abuse potential and withdrawal symptoms of the benzodiazepines, which are often diverted to recreational use because of their euphoric side effects. Combining eszopiclone with a serotonin calmative, such as quetiapine (Seroquel®), may increase eszopiclone's effectiveness.[citation needed]
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[edit] Pharmacodynamics
Eszopiclone is a hypnotic with a chemical structure unrelated to benzodiazepines or other drugs with known hypnotic properties. It is an agonist for the same family of receptors as benzodiazepines, but selectively binds to the receptor subtype known as omega¹. It is believed that this selectivity is responsible for its strong hypnotic effects and lack of significant anxiolytic properties. [1]
[edit] Pharmacokinetics
The pharmacokinetics of eszopiclone have been investigated in healthy subjects (adult and elderly) and in patients with hepatic disease or renal disease. In healthy subjects, the pharmacokinetic profile was examined after single doses of up to 7.5 mg and after once-daily administration of 1, 3, and 6 mg for 7 days. Eszopiclone is rapidly absorbed, with a time to peak concentration (T-max) of approximately 1 hour and a terminal-phase elimination half-life (t½) of approximately 6 hours. In healthy adults, Lunesta does not accumulate with once-daily administration, and its exposure is dose-proportional over the range of 1 to 6 mg. In patients 65 years of age and older, there is a slight prolonged elimination of eszopiclone (t½ of approximately 9 hours). Therefore, in elderly patients the starting dose of Lunesta should be decreased to 1 mg and the dose should not exceed 2 mg.
[edit] Absorption
Eszopiclone is rapidly absorbed following oral administration. Peak plasma concentrations are achieved within approximately 1 hour after oral administration. Eszopiclone is weakly bound to plasma protein (52-59%). The large free fraction suggests that eszopiclone disposition should not be affected by drug-drug interactions caused by protein binding. The blood-to-plasma ratio for eszopiclone is less than one, indicating no selective uptake by red blood cells.
[edit] Metabolism
Following oral administration, eszopiclone is extensively metabolized by oxidation and demethylation. The primary plasma metabolites are (S)-zopiclone-N-oxide and (S)-N-desmethyl zopiclone; the latter compound binds to GABA receptors with substantially lower potency than eszopiclone, and the former compound shows no significant binding to this receptor. In vitro studies have shown that CYP3A4 and CYP2E1 enzymes are involved in the metabolism of eszopiclone. Eszopiclone did not show any inhibitory potential on CYP450 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4 in cryopreserved human hepatocytes.
After oral administration, eszopiclone is eliminated with a mean t½ of approximately 6 hours. Up to 75% of an oral dose of racemic zopiclone is excreted in the urine, primarily as metabolites. A similar excretion profile would be expected for eszopiclone, the S-isomer of racemic zopiclone. Less than 10% of the orally administered eszopiclone dose is excreted in the urine as parent drug.
In healthy adults, administration of a 3 mg dose of eszopiclone after a high-fat meal resulted in no change in AUC, a reduction in mean Cmax of 21%, and delayed T-max by approximately 1 hour. The half-life remained unchanged, approximately 6 hours. The effects of Lunesta on sleep onset may be reduced if it is taken with or immediately after a high-fat/heavy meal. Sepracor, the drug's manufacturer and developer, recommend against using eszopiclone immediately following a meal due to this interference.
