Plasma concentrations and central nervous system effects of the new hypnotic agent zopiclone in patients with chronic liver disease.

Parker, G.; Roberts, CJ

doi:10.1111/j.1365-2125.1983.tb02159.x

Cited by 31 publications

(10 citation statements)

References 18 publications

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“…This drug was chosen because it has previously been shown that the clinical effects, as measured Correspondence: Dr K. S. Channer, Bristol Royal Infirmary, Bristol BS2 8HW, UK. by psychomotor tests, correlate well with the change in plasma concentration (Parker & Roberts, 1983).…”

Section: Introductionmentioning

confidence: 60%

The effect of posture at the time of administration on the central depressant effects of the new hypnotic zopiclone.

Channer¹,

Dent²,

Roberts³

1984

Brit J Clinical Pharma

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1 Nine healthy volunteers swallowed 7.5 mg zopiclone in the standing and lying positions on different occasions. Plasma concentrations of zopiclone and psychometric tests, including simple and complex reaction time, and critical flicker fusion threshold, were performed at regular intervals after drug administration. 2 The results show that when the drug was swallowed in the supine position, there was a significant delay in the onset of the impairment of psychomotor function, with prolongation in time to peak impairment by 30-40 min (P < 0.02). The overall impairment in psychomotor performance was found to be significantly less after administration of the drug in the supine position (P < 0.005). 3 Pharmacokinetic analysis revealed a prolongation in lag time of > 20 min before absorption began (P < 0.002) after supine drug administration, with a significantly lower rate constant of absorption (P < 0.02). Area under the plasma concentration-time curve extrapolated to infinity and rate constant of elimination were not significantly different between the two modes of administration. 4 We conclude that to obtain a rapid and complete effect from the hypnotic zopiclone, the tablet should be swallowed in the standing position.

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Section: Introductionmentioning

confidence: 60%

The effect of posture at the time of administration on the central depressant effects of the new hypnotic zopiclone.

Channer¹,

Dent²,

Roberts³

1984

Brit J Clinical Pharma

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“…The decrease in zopiclone plasma concentrations may be characterised by a bi-exponential equation of a 2-compartment model [3,22] or by a I-compartment modeJ.f20, 24] In healthy individuals, zopiclone terminal elimination half-life (ty,z) was found to range from 3.5 to 6.5 hours (table II). The elimination half-life of the N-oxide metabolite ranges from 3.5 to 6 hours, whereas that of the N-demethyl metabolite approximates 7 to 11 hours)n]…”

Section: Half-lifementioning

confidence: 99%

Clinical Pharmacokinetics of Zopiclone

Fernandez

Martin

Gimenez

et al. 1995

Clinical Pharmacokinetics

223

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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.

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“…In patients with hepatic impairment, increases were seen in elimination half-life (8.4 to 8.5 vs 3.5 to 5.3 hours in healthy volunteers), tmax (3.5 to 4 vs 0.5 to 2 hours) and bioavailability (97 vs 80%) Parker & Roberts 1983]. These changes reflect a reduction in the hepatic metabolic clearance of zopiclone in patients with cirrhosis as shown by the decrease in the metabolic ratio of the two main metabolites in patients with impaired hepatic function ).…”

Section: Effects Of Renal and Hepatic Dysfunctionmentioning

confidence: 98%

“…Absorption rates and times to Cmax (tmax) were similar in young (age 20 to 25 years) and elderly (age 65 to 85 years) volunteers; however, in a subgroup of volunteers aged between 74 and 85 years, Cmax values and areas under the plasma concentration-time curves (AUC) w~re increased (values presented graphically, Gaillot et at. Pharmacokinetic parameters of zopiclone after administration of a single oral 7.5mg dose in healthy volunteers (Caille et al 1984: Channer et al 1984Gaillot et al 1983Gaillot et al , 1987Houghton et al 1985;Parker & Roberts 1983;Stanley et al 1985) Parameter Absorption of zopiclone was delayed when the drug was administered to patients in the supine position although this did not have Table II.…”

Section: Absorption and Distributionmentioning

confidence: 99%

Zopiclone

Wadworth¹,

McTavish²

1993

Drugs & Aging

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Zopiclone is a cyclopyrrolone which is chemically unrelated to the benzodiazepines and is thought to act on the GABAA receptor complex at a site distinct from, but closely related to, the benzodiazepine binding site. The hypnotic efficacy of zopiclone administered as single oral doses has been demonstrated in patients undergoing next-day surgery and in patients with insomnia, and these studies have established an optimal dose of 7.5mg for elderly patients. Using this dose, clinical studies have shown that zopiclone improved sleep in elderly patients to a similar extent as triazolam 0.125 to 0.5mg, flurazepam 15mg, and nitrazepam 5mg. Studies that also included younger patients have shown that zopiclone 7.5mg is at least as effective as triazolam 0.25 or 0.5mg, and on most sleep parameters is comparable to temazepam 20mg, nitrazepam 5mg, flunitrazepam 2mg, and flurazepam 20mg. Zopiclone causes minimal impairment to psychomotor performance and mental alertness the morning after night-time administration. The drug is generally well tolerated by patients of all ages; the most frequently reported adverse effects being bitter taste and dry mouth. Treatment withdrawal due to adverse effects is seldom required and reports of rebound insomnia after zopiclone withdrawal are rare. While symptoms of physical dependence have not been observed in clinical studies, there have been isolated reports of physical dependence in patients with a history of substance abuse. Although the latter finding should be kept in mind, it appears that zopiclone has a low dependence liability. Thus, with its short duration of action and good tolerability profile, zopiclone is a well established alternative to the benzodiazepine hypnotics and may be particularly beneficial in those patients unable or unwilling to tolerate the residual effects associated with many other hypnotic agents.

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Plasma concentrations and central nervous system effects of the new hypnotic agent zopiclone in patients with chronic liver disease.

Cited by 31 publications

References 18 publications

The effect of posture at the time of administration on the central depressant effects of the new hypnotic zopiclone.

The effect of posture at the time of administration on the central depressant effects of the new hypnotic zopiclone.

Clinical Pharmacokinetics of Zopiclone

Zopiclone

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