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Zolpidem metabolism in vitro : responsible cytochromes, chemical inhibitors, and in vivo correlations
Author(s) -
Von Moltke Lisa L.,
Greenblatt David J.,
Granda Brian W.,
Duan Su Xiang,
Grassi Jeffrey M.,
Venkatakrishnan Karthik,
Harmatz Jerold S.,
Shader Richard I.
Publication year - 1999
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1046/j.1365-2125.1999.00953.x
Subject(s) - zolpidem , ketoconazole , metabolite , microsome , pharmacology , cyp1a2 , chemistry , biotransformation , cytochrome p450 , cyp3a4 , in vitro , biochemistry , metabolism , biology , enzyme , microbiology and biotechnology , antifungal , insomnia
Aims To determine the human cytochromes mediating biotransformation of the imidazopyridine hypnotic, zolpidem, and the clinical correlates of the findings.Methods Kinetic properties of zolpidem biotransformation to its three hydroxylated metabolites were studied in vitro using human liver microsomes and heterologously expressed individual human cytochromes.Results The metabolic product termed M‐3 accounted for more than 80% of net intrinsic clearance by liver microsomes in vitro. Microsomes containing human cytochromes CYP1A2, 2C9, 2C19, 2D6, and 3 A4 expressed by cDNA‐transfected human lymphoblastoid cells mediated zolpidem metabolism in vitro. The kinetic profile for zolpidem metabolite formation by each individual cytochrome was combined with estimated relative abundances based on immunological quantification, yielding projected contributions to net intrinsic clearance of: 61% for 3 A4, 22% for 2C9, 14% for 1A2, and less than 3% for 2D6 and 2C19. These values were consistent with inhibitory effects of ketoconazole and sulfaphenazole on zolpidem biotransformation by liver microsomes. Ketoconazole had a 50% inhibitory concentration (IC 50 ) of 0.61 μm vs formation of the M‐3 metabolite of zolpidem in vitro; in a clinical study, ketoconazole coadministration reduced zolpidem oral clearance by ≈40%, somewhat less than anticipated based on the IC 50 value and total plasma ketoconazole levels, but much more than predicted based on unbound plasma ketoconazole levels.Conclusions The incomplete dependence of zolpidem clearance on CYP3A activity has clinical implications for susceptibility to metabolic inhibition.