OXIDATIVE-METABOLISM OF ZOLPIDEM BY HUMAN LIVER CYTOCHROME P450S

The aim of this study was to identify the form(s) of cytochrome P450 ( CYP) responsible for the biotransformation of zolpidem to its alcohol derivatives which, after rapid conversion to carboxylic acids, represe nts the main way of metabolism in humans. In human liver microsomes, z olpidem was converted to alcohol derivatives, Production of these corr elated with the level of CYP3A4 and with cyclosporin oxidation and ery thromycin N-demethylation activities, but not with the level of CYP1A2 nor with ethoxyresorufin O-deethylation or S-mephenytoin 4'-hydroxyla tion activities. Liver microsomes from CYP2D6-deficient patients exhib ited normal activity. Production of alcohol derivatives was significan tly inhibited by anti-CYP3A antibodies and by ketoconazole. Antibodies directed against other CYP forms (including CYP1A1, CYP1A2, CYP2A6, C YP2B4, and CYP2C8), and CYP-specific substrates or inhibitors (includi ng propranolol, coumarin, mephenytoin, sulfaphenazole, quinidine, anil ine, and lauric acid) produced a moderate or no inhibitory effect, cDN A-expressed CYP3A4 and CYP1A2 generated significant amounts of one of the alcohol derivatives, whereas CYP2D6 generated both of them in simi lar amounts. In human hepatocytes in primary culture, zolpidem was ext ensively and almost exclusively converted to one of the carboxylic aci d derivatives, the main species identified in vivo. Treatment of cells with inducers of CYPIA (beta-naphthoflavone) and CYP3A (rifampicin an d phenobarbital) greatly increased the rate of production of this meta bolite. We conclude that the formation of alcohol derivatives of zolpi dem is rate-limiting and principally mediated by CYP3A4, Both CYP1A2 a nd CYP2D6 participate in alcohol formation; but, because of their low relative level of expression in the human liver, their contribution is minor.