PT  - JOURNAL ARTICLE
AU  - Bojan Lalovic
AU  - Brian Phillips
AU  - Linda L. Risler
AU  - William Howald
AU  - Danny D. Shen
TI  - QUANTITATIVE CONTRIBUTION OF CYP2D6 AND CYP3A TO OXYCODONE METABOLISM IN HUMAN LIVER AND INTESTINAL MICROSOMES
AID  - 10.1124/dmd.32.4.447
DP  - 2004 Apr 01
TA  - Drug Metabolism and Disposition
PG  - 447--454
VI  - 32
IP  - 4
4099  - http://dmd.aspetjournals.org/content/32/4/447.short
4100  - http://dmd.aspetjournals.org/content/32/4/447.full
SO  - Drug Metab Dispos2004 Apr 01; 32
AB  - 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