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Quantitative Contribution of CYP2D6 and CY3PA To Oxycodone Metabolism in Human Liver and Intestinal

Quantitative Contribution of CYP2D6 and CY3PA To Oxycodone Metabolism in Human Liver and Intestinal

  1. Jatelka
    Drug Metabolism and Disposition 32:447–454, 2004

    Bojan Lalovic, Brian Phillips, Linda L. Risler, William Howald, and Danny D. Shen

    Looks at the metabolism of Oxycodone and the contribution of various cytochrome enzymes.

    Oxycodone undergoes N-demethylation to noroxycodone and O-demethylation to oxymorphone. The cytochrome P450 (P450) iso-forms capable of mediating the oxidation of oxycodone to oxymor-phone and noroxycodone were identified using a panel of recombinant human P450s. CYP3A4 and CYP3A5 displayed the highest activity for oxycodone N-demethylation; intrinsic clear-ance for CYP3A5 was slightly higher than that for CYP3A4. CYP2D6 had the highest activity for O-demethylation. Multienzyme, Michaelis-Menten kinetics were observed for both oxidative reac-tions in microsomes prepared from five human livers. Inhibition with ketoconazole showed that CYP3A is the high affinity enzyme for oxycodone N-demethylation; ketoconazole inhibited >90% of noroxycodone formation at low substrate concentrations. CYP3A-mediated noroxycodone formation exhibited a mean Km of 600  119 M and a Vmax that ranged from 716 to 14523 pmol/mg/min. Contribution from the low affinity enzyme(s) did not exceed 8% of total intrinsic clearance for N-demethylation. Quinidine inhibition showed that CYP2D6 is the high affinity enzyme for O-demethyl-ation with a mean Km of 130  33 M and a Vmax that ranged from 89 to 356 pmol/mg/min. Activity of the low affinity enzyme(s) ac-counted for 10 to 26% of total intrinsic clearance for O-demethyl-ation. On average, the total intrinsic clearance for noroxycodone formation was 8 times greater than that for oxymorphone forma-tion across the five liver microsomal preparations (10.5 l/min/mg versus 1.5 l/min/mg). Experiments with human intestinal mucosal microsomes indicated lower N-demethylation activity (20–50%) compared with liver microsomes and negligible O-demethylation activity, which predict a minimal contribution of intestinal mucosa in the first-pass oxidative metabolism of oxycodone.