Characterization of oxycodone in vitro metabolism by human cytochromes P450 and UDP-glucuronosyltransferases.
The hepatic metabolism of oxycodone by cytochromes P450 (CYP) and the UDP-glucuronosyltransferases (UGT), the main metabolic enzymes of phase I and phase II, respectively, was assessed in vitro. The N-demethylation by CYP3A4/5 and the O-demethylation by CYP2D6 in human liver microsomes (HLM) followed Michaelis-Menten kinetics, with intrinsic clearances of 1.46μL/min/mg and 0.35μL/min/mg, respectively. Although noroxycodone and oxymorphone mainly contribute to the elimination of oxycodone, the simulated total in vivo clearance using in vitro phase I metabolism was underestimated. For the first time, metabolism of oxycodone by UGT was deeply investigated using HLM, recombinant enzymes and selective inhibitors. Oxycodone-glucuronide was mainly produced by UGT2B7 (Km=762±153μM, Vmax=344±20 peak area/min/mg) and to a lesser extent by UGT2B4 (Km=2454±497μM, Vmax=201±19 peak area/min/mg). Finally, the kinetics of the drug-drug interactions were assessed using two CYP and UGT cocktail approaches. Incubations of HLM with phase I and phase II drug probes showed that oxycodone mainly decreased the in vitro activities of CYP2D6, CYP3A4/5, UGT1A3, UGT1A6 and UGT2B subfamily with an important impact on UGT2B7.
School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Rue Michel Servet 1, 1211 Geneva 4, Switzerland.
Stéphanie
S
Romand
School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Rue Michel Servet 1, 1211 Geneva 4, Switzerland.
Dany
D
Spaggiari
School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Rue Michel Servet 1, 1211 Geneva 4, Switzerland; Service of Clinical Pharmacology and Toxicology, Department of Anesthesiology, Pharmacology and Intensive Care, Geneva University Hospitals, 1211 Geneva, Switzerland.
Niloufar
N
Marsousi
Service of Clinical Pharmacology and Toxicology, Department of Anesthesiology, Pharmacology and Intensive Care, Geneva University Hospitals, 1211 Geneva, Switzerland.
Caroline
C
Samer
Service of Clinical Pharmacology and Toxicology, Department of Anesthesiology, Pharmacology and Intensive Care, Geneva University Hospitals, 1211 Geneva, Switzerland.
Jules
J
Desmeules
Service of Clinical Pharmacology and Toxicology, Department of Anesthesiology, Pharmacology and Intensive Care, Geneva University Hospitals, 1211 Geneva, Switzerland.
Youssef
Y
Daali
School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Rue Michel Servet 1, 1211 Geneva 4, Switzerland. Electronic address: serge.rudaz@unige.ch.
Serge
S
Rudaz
D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D020719:Glucuronides; D014453:Glucuronosyltransferase / Q000378:metabolism*; D006801:Humans; D008862:Microsomes, Liver; D010098:Oxycodone
D020719:Glucuronides; D003577:Cytochrome P-450 Enzyme System; D010098:Oxycodone; D014453:Glucuronosyltransferase
Cytochromes P450; In vitro metabolism; Oxycodone; UDP-glucuronosyltransferases