Zolpidem metabolism in vitro: responsible cytochromes, chemical inhibitors, and in vivo correlations

Aims To determine the human cytochromes mediating biotransformation of the imidazopyridine hypnotic, zolpidem, and the clinical correlates of the find ings. Methods Kinetic properties of zolpidem biotransformation to its three hydro xylated 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 hu man cytochromes CYP1A2, 2C9, 2C19, 2D6, and 3 A4 expressed by cDNA-transfec ted human lymphoblastoid cells mediated zolpidem metabolism in vitro. The k inetic profile for zolpidem metabolite formation by each individual cytochr ome 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. Ketoc onazole had a 50% inhibitory concentration (IC50) of 0.61 mu M vs formation of the M-3 metabolite of zolpidem in vitro; in a clinical study, ketoconaz ole coadministration reduced zolpidem oral clearance by approximate to 40%, somewhat less than anticipated based on the IC50 value and total plasma ke toconazole levels, but much more than predicted based on unbound plasma ket oconazole levels. Conclusions The incomplete dependence of zolpidem clearance on CYP3A activi ty has clinical implications for susceptibility to metabolic inhibition.