Titre du document / Document title

Quantitative contribution of CYP2D6 and CYP3A to oxycodone metabolism in human liver and intestinal microsomes

Auteur(s) / Author(s)

LALOVIC Bojan ^{(1 2)} ; PHILLIPS Brian ⁽²⁾ ; RISLER Linda L. ⁽²⁾ ; HOWALD William ⁽³⁾ ; SHEN Danny D. ^{(1 2 4)} ;

Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)

⁽¹⁾ Department of Pharmaceutics, University of Washington, Seattle, Washington, ETATS-UNIS
⁽²⁾ Departments of PharmaceuticClinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, ETATS-UNIS
⁽³⁾ Department of Medicinal Chemistry, University of Washington, Seattle, Washington, ETATS-UNIS
⁽⁴⁾ Department of Pharmacy, University of Washington, Seattle, Washington, ETATS-UNIS

Résumé / Abstract

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 K_m of 600 ± 119 μM and a V_max 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 K_m of 130 ± 33 μM and a V_max 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.

Revue / Journal Title

Drug metabolism and disposition   ISSN 0090-9556   CODEN DMDSAI 

Source / Source

2004, vol. 32, n^o4, pp. 447-454 [8 page(s) (article)] (39 ref.)

Langue / Language

Anglais

Editeur / Publisher

American Society for Pharmacology and Experimental Therapeutics, Bethesda, MD, ETATS-UNIS  (1973) (Revue)

Mots-clés anglais / English Keywords

Digestive system ; Pharmacokinetics ; Opiates ; Narcotic analgesic ; In vitro ; Microsome ; Gut ; Liver ; Human ; Metabolism ; Oxycodone ; Isozyme ; Cytochrome P450 ; Quantitative analysis ; Oxidation ;

Mots-clés français / French Keywords

Appareil digestif ; Pharmacocinétique ; Opiacés ; Analgésique narcotique ; In vitro ; Microsome ; Intestin ; Foie ; Homme ; Métabolisme ; Oxycodone ; Isozyme ; Cytochrome P450 ; Analyse quantitative ; Oxydation ;

Mots-clés espagnols / Spanish Keywords

Aparato digestivo ; Farmacocinética ; Opiados ; Analgésico narcotico ; In vitro ; Microsoma ; Intestino ; Hígado ; Hombre ; Metabolismo ; Oxicodona ; Isozima ; Citocromo P450 ; Análisis cuantitativo ; Oxidación ;

Localisation / Location

INIST-CNRS, Cote INIST : 16545, 35400011146231.0130