Role of individual human cytochrome P450 enzymes in the in vitro metabolism of hydromorphone.
1. The aim was to identify the individual human cytochrome P450 (CYP) enzymes responsible for the in vitro N-demethylation of hydromorphone and to determine the potential effect of the inhibition of this metabolic pathway on the formation of other hydromorphone metabolites. 2. Hydromorphone was metabolized to norhydromorphone (apparent Km = 206 - 822 microM, Vmax = 104 - 834 pmol min(-1) mg(-1) protein) and dihydroisomorphine (apparent Km = 62 - 557 microM, Vmax = 17 - 122 pmol min(-1) mg(-1) protein) by human liver microsomes. 5. In pooled human liver microsomes, troleandomycin, ketoconazole and sulfaphenazole reduced norhydromorphone formation by an average of 45, 50 and 25%, respectively, whereas furafylline, quinidine and omeprazole had no effect. In an individual liver microsome sample with a high CYP3A protein content, troleandomycin and ketoconazole inhibited norhydromorphone formation by 80%. 5. The reduction in norhydromorphone formation by troleandomycin and ketoconazole was accompanied by a stimulation in dihydroisomorphine production. Recombinant CYP3A4, CYP3A5, CYP2C9 and CYP2D6, but not CYP1A2, catalysed norhydromorphone formation, whereas none of these enzymes was active in dihydroisomorphine formation. 6. In summary, CYP3A and, to a lesser extent, CYP2C9 catalysed hydromorphone N-demethylation in human liver microsomes. The inhibition of norhydromorphone formation by troleandomycin and ketoconazole resulted in a stimulation of microsomal dihydroisomorphine formation.
Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
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Benetton
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Borges
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Chang
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McErlane
D002478:Cells, Cultured; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D004091:Hydromorphone / Q000737:chemistry* / Q000378:metabolism*; D007700:Kinetics; D008862:Microsomes, Liver / Q000737:chemistry* / Q000201:enzymology*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D003577:Cytochrome P-450 Enzyme System; D004091:Hydromorphone