Abstract
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) andN-oxide-zopiclone (NO-Z) with the followingKm and Vm 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 α-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 6β-hydroxylation (CYP3A activity, r = 0.95 and 0.92, respectively; p = .0001), and ND-Z was highly correlated to CYP2C8 activity (paclitaxel 6α-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.
Footnotes
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Send reprint requests to: Dr. Laurent Becquemont, Faculté de Médecine, Saint Antoine Paris VI, Service de Pharmacologie, 27 Rue de Chaligny, 75012 Paris, France. E-mail:becquemo{at}b3e.jussieu.fr
- Abbreviations used are::
- NO-Z
- N-oxide-zopiclone
- ND-Z
- N-desmethyl-zopiclone
- CYP
- cytochrome P-450
- rH-CYP
- recombinant human cytochrome P-450
- Received December 31, 1998.
- Accepted May 7, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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