CLINICAL PHARMACOKINETICS OF ZOPICLONE

Zopiclone is a cyclopyrrolone hypnotic agent. It possesses a chiral ce ntre and is commercially available as a racemic mixture. Methods invol ving high performance liquid chromatography (HPLC), gas chromatography , capillary electrophoresis (CE) and high performance thin layer chrom atography have been developed for the quantitation of zopiclone and it s 2 main metabolites in biological samples. For the chiral determinati on of the enantiomers of zopiclone and its metabolites, HPLC and CE me thods are available. After oral administration, zopiclone is rapidly a bsorbed, with a bioavailability of approximately 80%. The plasma prote in binding of zopiclone has been reported to be between 45 and 80%. Zo piclone is rapidly and widely distributed to body tissues including th e brain, and is excreted in urine; saliva and breast milk. Zopiclone i s partly metabolised in the liver to form an inactive N-demethylated d erivative and an active N-oxide metabolite. In addition, approximately 50% of the administered dose is decarboxylated and excreted via the l ungs. Less than 7% of the administered dose is renally excreted as unc hanged zopiclone. In urine, the N-demethyl and N-oxide metabolites acc ount for 30% of the initial dose. The terminal elimination half-life ( t1/2(z)) Of zopiclone ranges from 3.5 to 6.5 hours. The pharmacokineti cs of zopiclone in humans are stereoselective. After oral administrati on of the racemic mixture, C-max (time to maximum plasma concentration ), AUC (area under the plasma time-concentration curve) and t1/2(z) va lues are higher for the dextrorotatory enantiomer owing to the slower total clearance and smaller volume of distribution (corrected by the b ioavailability), 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 antip odes. The pharmacokinetics of zopiclone are altered by aging and are i nfluenced by renal and hepatic functions. Drug interactions have been observed with erythromycin, trimipramine and carbamazepine.