Clinical Pharmacokinetics of Zopiclone

Abstract

Zopiclone is a cyclopyrrolone hypnotic agent. It possesses a chiral centre and is commercially available as a racemic mixture. Methods involving high performance liquid chromatography (HPLC), gas chromatography, capillary electrophoresis (CE) and high performance thin layer chromatography have been developed for the quantitation of zopiclone and its 2 main metabolites in biological samples. For the chiral determination of the enantiomers of zopiclone and its metabolites, HPLC and CE methods are available. After oral administration, zopiclone is rapidly absorbed, with a bioavailability of approximately 80%. The plasma protein binding of zopiclone has been reported to be between 45 and 80%. Zopiclone is rapidly and widely distributed to body tissues including the brain, and is excreted in urine, saliva and breast milk. Zopiclone is partly metabolised in the liver to form an inactive N-demethylated derivative and an active N-oxide metabolite. In addition, approximately 50% of the administered dose is decarboxylated and excreted via the lungs. Less than 7% of the administered dose is renally excreted as unchanged zopiclone. In urine, the N-demethyl and N-oxide metabolites account for 30% of the initial dose. The terminal elimination half-life (t1/2z) of zopiclone ranges from 3.5 to 6.5 hours. The pharmacokinetics of zopiclone in humans are stereoselective. After oral administration of the racemic mixture, Cmax (time to maximum plasma concentration), AUC (area under the plasma time-concentration curve) and t1/2z values are higher for the dextrorotatory enantiomer owing to the slower total clearance and smaller volume of distribution (corrected by the bioavailability), compared with the levorotatory enantiomer. In urine, the concentrations of the dextrorotatory enantiomers of the N-demethyl and N-oxide metabolites are higher than those of the respective antipodes. The pharmacokinetics of zopiclone are altered by aging and are influenced by renal and hepatic functions. Drug interactions have been observed with erythromycin, trimipramine and carbamazepine.

Pharmacologically Active Drug Metabolites: Impact on Drug Discovery and Pharmacotherapy

“…Zopiclone is a sedative agent active at the benzodiazepine receptor family. In one paper it was claimed that the N-oxide metabolite possessed activity and the N-desmethyl did not (Fernandez et al, 1995). However in receptor binding studies (using rat), the N-oxide was at least two orders of magnitude less potent than parent (Trifiletti and Snyder, 1984), and the desmethyl was one order of magnitude less potent (Fig.…”

In Vivo Pharmacological Characterization of Indiplon, a Novel Pyrazolopyrimidine Sedative-Hypnotic

“…Thus, for example, zolpidem has a moderate affinity for ␣1-containing GABA A receptors in radioligand binding experiments (10 -100 nM; Arbilla et al, 1985;Smith et al, 2001;Sullivan et al, 2004), is fully efficacious (Smith et al, 2001;Sullivan et al, 2004), has selectivity for GABA A receptors containing the ␣1 subunit (Damgen and Luddens, 1999;Smith et al, 2001), produces sedative activity in animals that is mediated through ␣1 subunit-containing GABA A receptors , and has a half-life in rodents and humans after oral administration of 2 to 3 h (Gaudreault et al, 1995;Greenblatt et al, 1998). Zopiclone displays a similar efficacy profile in animal tests (Perrault et al, 1990), but it has only marginal selectivity for GABA A receptors containing the ␣1 subunit (Damgen and Luddens, 1999;Smith et al, 2001) and its half-life in humans of 3.5 to 6.5 h (Fernandez et al, 1995) has been associated with next day hangover effects, including impaired driving ability (Bocca et al, 1999;Vermeeren et al, 2002). Zaleplon has a half-life of 1 h in humans after oral administration (Greenblatt et al, 1998); however, this compound has a lower affinity than zolpidem at benzodiazepine binding sites and a reduced selectivity for ␣1 subunit-containing GABA A receptors (Damgen and Luddens, 1999).…”

Zopiclone degradation in biological samples : Characteristics and consequences in forensic toxicology

“…Elimination half-life (t 1/2 ) of ZOP falls within the range of 3.5 to 6.5 hours. No gender difference in pharmacokinetics of ZOP has been observed, although in patients with liver or renal dysfunction small differences exist and the plasma half-life of ZOP increases with age [92,93].…”

“…After oral administration of the racemic drug, ZOP is rapidly absorbed from the gastrointestinal tract, with a bioavailability of approximately 80% [92]. Plasma protein binding of ZOP was reported as 45% in one study [93] and 80% in another [94].…”

“…In the liver ZOP is partly metabolized to an inactive N-demethylated (13-20% of dose) and an active N-oxide metabolite (9-18% of dose) [92]. The cytochrome P-450 (CYP) enzymes CYP3A4 and CYP2C8 are involved in the metabolism of ZOP.…”