title: Zolpidem metabolism in vitro: responsible cytochromes, chemical inhibitors, and in vivo correlations.
abstract: OBJECTIVE
  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 (IC50 ) of 0.61 microm vs formation of the M-3 metabolite of zolpidem in vitro; in a clinical study, ketoconazole coadministration reduced zolpidem oral clearance by approximately 40%, somewhat less than anticipated based on the IC50 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.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA 02111, USA.
authors.forename: L L
authors.initials: LL
authors.lastname: Von Moltke
authors.forename: D J
authors.initials: DJ
authors.lastname: Greenblatt
authors.forename: B W
authors.initials: BW
authors.lastname: Granda
authors.forename: S X
authors.initials: SX
authors.lastname: Duan
authors.forename: J M
authors.initials: JM
authors.lastname: Grassi
authors.forename: K
authors.initials: K
authors.lastname: Venkatakrishnan
authors.forename: J S
authors.initials: JS
authors.lastname: Harmatz
authors.forename: R I
authors.initials: RI
authors.lastname: Shader
mesh_terms: D001711:Biotransformation; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006993:Hypnotics and Sedatives / Q000378:metabolism*; D066298:In Vitro Techniques; D007654:Ketoconazole / Q000494:pharmacology; D008657:Metabolic Clearance Rate; D008862:Microsomes, Liver / Q000378:metabolism*; D011725:Pyridines / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured; D000077334:Zolpidem
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D006993:Hypnotics and Sedatives; D011725:Pyridines; D000077334:Zolpidem; D003577:Cytochrome P-450 Enzyme System; D007654:Ketoconazole