Vol. 27, Issue 9, 1068-1073, September 1999

Cytochrome P-450 3A4 and 2C8 Are Involved in Zopiclone Metabolism

Laurent Becquemont, Said Mouajjah, Olivier Escaffre, Philippe Beaune, Christian Funck-Brentano, and Patrice Jaillon

Clinical Pharmacology Unit (L.B., S.M., O.E., C.F.-B., P.J.), Saint Antoine University Hospital, School of Medicine Paris 6, France; and Institut National de la Santé et de la Recherche Médicale U 490 (P.B.), Saint-Pères University, School of Medicine Paris 5, France

Zopiclone is a widely prescribed, nonbenzodiazepine hypnotic that is extensively metabolized by the liver in humans. The aim of the present study was to identify the human cytochrome P-450 (CYP) isoforms involved in zopiclone metabolism in vitro. Zopiclone metabolism was studied with different human liver microsomes and a panel of heterologously expressed human CYPs (CYP1A2, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, and 3A4). In human liver microsomes, zopiclone was metabolized into N-desmethyl-zopiclone (ND-Z) and N-oxide-zopiclone (NO-Z) with the following K_m and V_m of 78 ± 5 and 84 ± 19 µM, 45 ± 1 and 54 ± 5 pmol/min/mg for ND-Z and NO-Z generation, respectively. Ketoconazole (CYP3A inhibitor) inhibited ~40% of the generation of both metabolites, sulfaphenazole (CYP2C inhibitor) inhibited the formation of ND-Z, whereas -naphtoflavone (CYP1A), quinidine (CYP2D6), and chlorzoxazone (CYP2E1) did not affect zopiclone metabolism. The generation of ND-Z and NO-Z were highly correlated to testosterone 6-hydroxylation (CYP3A activity, r = 0.95 and 0.92, respectively; p = .0001), and ND-Z was highly correlated to CYP2C8 activity (paclitaxel 6-hydroxylase; r = 0.76, p = .004). Recombinant CYP2C8 had the highest enzymatic activity toward zopiclone metabolism into both its metabolites, followed by CYP2C9 and 3A4. CYP3A4 is the major enzyme involved in zopiclone metabolism in vitro, and CYP2C8 contributes significantly to ND-Z formation.