Cytochrome P-450 3A4 and 2C8 are involved in zopiclone metabolism

Zopiclone is a widely prescribed, nonbenzodiazepine hypnotic that is extens ively 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 (CYP1A 2, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, and 3A4). In human liver microsomes, zop iclone was metabolized into N-desmethyl-zopiclone (ND-Z) and N-oxide-zopicl one (NO-Z) with the following K-m and V-m of 78 +/- 5 and 84 +/- 19 mu M, 4 5 +/- 1 and 54 +/- 5 pmol/min/mg for ND-Z and NO-Z generation, respectively . Ketoconazole (CYP3A inhibitor) inhibited similar to 40% of the generation of both metabolites, sulfaphenazole (CYP2C inhibitor) inhibited the format ion of ND-Z, whereas alpha-naphtoflavone (CYP1A), quinidine (CYP2D6), and c hlorzoxazone (CYP2E1) did not affect zopiclone metabolism. The generation o f ND-Z and NO-Z were highly correlated to testosterone 6 beta-hydroxylation (CYP3A activity, r = 0.95 and 0.92, respectively; p = .0001), and ND-Z was highly correlated to CYP2C8 activity (paclitaxel 6 alpha-hydroxylase; r = 0.76, p = .004). Recombinant CYP2C8 had the highest enzymatic activity towa rd zopiclone metabolism into both its metabolites, followed by CYP2C9 and 3 A4. CYP3A4 is the major enzyme involved in zopiclone metabolism in vitro, a nd CYP2C8 contributes significantly to ND-Z formation.