Document Detail

Oxidative metabolism of zolpidem by human liver cytochrome P450S.
MedLine Citation:
PMID:  8591727     Owner:  NLM     Status:  MEDLINE    
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, represents the main way of metabolism in humans. In human liver microsomes, zolpidem was converted to alcohol derivatives. Production of these correlated with the level of CYP3A4 and with cyclosporin oxidation and erythromycin N-demethylation activities, but not with the level of CYP1A2 nor with ethoxyresorufin O-deethylation or S-mephenytoin 4'-hydroxylation activities. Liver microsomes from CYP2D6-deficient patients exhibited normal activity. Production of alcohol derivatives was significantly inhibited by anti-CYP3A antibodies and by ketoconazole. Antibodies directed against other CYP forms (including CYP1A1, CYP1A2, CYP2A6, CYP2B4, and CYP2C8), and CYP-specific substrates or inhibitors (including propranolol, coumarin, mephenytoin, sulfaphenazole, quinidine, aniline, and lauric acid) produced a moderate or no inhibitory effect. cDNA-expressed CYP3A4 and CYP1A2 generated significant amounts of one of the alcohol derivatives, whereas CYP2D6 generated both of them in similar amounts. In human hepatocytes in primary culture, zolpidem was extensively and almost exclusively converted to one of the carboxylic acid derivatives, the main species identified in vivo. Treatment of cells with inducers of CYP1A (beta-naphthoflavone) and CYP3A (rifampicin and phenobarbital) greatly increased the rate of production of this metabolite. We conclude that the formation of alcohol derivatives of zolpidem is rate-limiting and principally mediated by CYP3A4. Both CYP1A2 and CYP2D6 participate in alcohol formation; but, because of their low relative level of expression in the human liver, their contribution is minor.
L Pichard; G Gillet; C Bonfils; J Domergue; J P Thénot; P Maurel
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Publication Detail:
Type:  In Vitro; Journal Article    
Journal Detail:
Title:  Drug metabolism and disposition: the biological fate of chemicals     Volume:  23     ISSN:  0090-9556     ISO Abbreviation:  Drug Metab. Dispos.     Publication Date:  1995 Nov 
Date Detail:
Created Date:  1996-04-03     Completed Date:  1996-04-03     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  9421550     Medline TA:  Drug Metab Dispos     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  1253-62     Citation Subset:  IM    
INSERM U-128, (CNRS), Montpellier, France.
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MeSH Terms
Cells, Cultured
Cytochrome P-450 Enzyme System / biosynthesis,  immunology,  metabolism*
DNA, Complementary / biosynthesis
Enzyme Induction / drug effects
Hypnotics and Sedatives / metabolism*
Liver / enzymology*,  metabolism
Microsomes, Liver / enzymology
Middle Aged
Mixed Function Oxygenases / metabolism
Pyridines / metabolism*
Reg. No./Substance:
0/DNA, Complementary; 0/Hypnotics and Sedatives; 0/Pyridines; 82626-48-0/zolpidem; 9035-51-2/Cytochrome P-450 Enzyme System; EC 1.-/Mixed Function Oxygenases

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