TY - JOUR T1 - QUANTITATIVE CONTRIBUTION OF CYP2D6 AND CYP3A TO OXYCODONE METABOLISM IN HUMAN LIVER AND INTESTINAL MICROSOMES JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 447 LP - 454 DO - 10.1124/dmd.32.4.447 VL - 32 IS - 4 AU - Bojan Lalovic AU - Brian Phillips AU - Linda L. Risler AU - William Howald AU - Danny D. Shen Y1 - 2004/04/01 UR - http://dmd.aspetjournals.org/content/32/4/447.abstract N2 - Oxycodone undergoes N-demethylation to noroxycodone and O-demethylation to oxymorphone. The cytochrome P450 (P450) isoforms capable of mediating the oxidation of oxycodone to oxymorphone and noroxycodone were identified using a panel of recombinant human P450s. CYP3A4 and CYP3A5 displayed the highest activity for oxycodone N-demethylation; intrinsic clearance 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 reactions 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 μM 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-demethylation with a mean Km of 130 ± 33 μM and a Vmax that ranged from 89 to 356 pmol/mg/min. Activity of the low affinity enzyme(s) accounted for 10 to 26% of total intrinsic clearance for O-demethylation. On average, the total intrinsic clearance for noroxycodone formation was 8 times greater than that for oxymorphone formation across the five liver microsomal preparations (10.5 μl/min/mg versus 1.5 μl/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. The American Society for Pharmacology and Experimental Therapeutics ER -