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Pharmacokinetics and Metabolism of Zopiclone (1983)

Pharmacokinetics and Metabolism of Zopiclone (1983)

  1. Calliope
    Pharmacology. 27 Suppl 2: 76-91.

    Gaillot J, Heusse D, Hougton GW, Marc Aurele J, Dreyfus JF.

    Abstract
    Pharmacokinetics and metabolism of a new hypnotic, zopiclone (ZD) were studied under the following conditions: (1) rats and dogs were given oral doses of the molecule, 14C-labeled either on the side chain or on the pyrrolopyrazine nucleus; (2) rats, rabbits and dogs were given increasing doses oral doses of the cold compound; (3) human subjects in various physiopathological situations – young and elderly healthy volunteers, patients with liver or renal impairments, nursing mothers – were given single or repeated doses, p.o. or i.v. (range 3.5-15 mg). ZD is rapidly and efficiently absorbed: its bioavailability was > 75% in all species except rats, where a first-pass effect of about 65% was recorded. Plasma protein binding is about 45%. The radioactive material rapidly diffuses from the vascular compartment, with marked affinity for the brain. Plasma kinetics of ZD are generally well described by a two-compartment open model; in man, terminal half-life id 4-5 h; total body clearance is large (300ml/mn), renal clearance very low (10ml/min). The relationship between doses and concentrations, doses and urinary excretions of unchanged compound and major metabolites was linear in all species except rabbits. The major metabolic routes involve decarboxylation affecting more than 50% of dose (rats and dogs), N-desmethylation and N-oxydation—more than 30% as N-desmethyl and N-oxide derivatives in urine (humans). Due to intensive metabolism, only 7-10% of the dose is recovered in urine and feces as unchanged compounds (all species). In nursing mothers, milk and plasma kinetics of ZD are similar with a milk/plasma ratio of around 0.80. In human volunteers, plasma half-life of ZD increases with age, while patients with liver or renal impairments show little or no modification of pharmacokinetic parameters.
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