QUANTITATIVE CONTRIBUTION OF CYP2D6 AND CYP3A TO OXYCODONE METABOLISM IN HUMAN LIVER AND INTESTINAL MICROSOMES

• Published in: Drug metabolism and disposition 2004-04, Vol.32 (4), p.447-454
• Main Authors: Lalovic, Bojan, Phillips, Brian, Risler, Linda L., Howald, William, Shen, Danny D.
• Format: Article
• Language: English
• Subjects: Analgesics; Aryl Hydrocarbon Hydroxylases - genetics; Aryl Hydrocarbon Hydroxylases - metabolism; Aryl Hydrocarbon Hydroxylases - pharmacology; Biological and medical sciences; Biotransformation; Cytochrome P-450 CYP2D6 - genetics; Cytochrome P-450 CYP2D6 - metabolism; Cytochrome P-450 CYP2D6 - pharmacology; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System - genetics; Cytochrome P-450 Enzyme System - metabolism; DNA, Complementary - genetics; Humans; Intestinal Mucosa - metabolism; Intestines - drug effects; Intestines - ultrastructure; Ketoconazole - metabolism; Ketoconazole - pharmacology; Kinetics; Medical sciences; Metabolic Clearance Rate; Methylation - drug effects; Microsomes - drug effects; Microsomes - metabolism; Microsomes, Liver - chemistry; Microsomes, Liver - drug effects; Microsomes, Liver - metabolism; Molecular Structure; Morphinans - antagonists & inhibitors; Morphinans - chemistry; Morphinans - metabolism; Neuropharmacology; Oxidoreductases, N-Demethylating - genetics; Oxidoreductases, N-Demethylating - metabolism; Oxidoreductases, N-Demethylating - pharmacology; Oxycodone - metabolism; Oxycodone - pharmacology; Oxymorphone - chemistry; Oxymorphone - metabolism; Pharmacology. Drug treatments; Protein Binding - drug effects; Quinidine - adverse effects; Quinidine - antagonists & inhibitors; Quinidine - pharmacology
• ISSN: 0090-9556; 1521-009X
• DOI: 10.1124/dmd.32.4.447

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.