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Characterization of oxycodone in vitro metabolism by human cytochromes P450 and UDP-glucuronosyltransferases

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Published in Journal of Pharmaceutical and Biomedical Analysis. 2016
Abstract 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.
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PMID: 27692933
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Article (Published version) (924 Kb) - public document Free access
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Research group Groupe Desmeules Jules (pharmacologie/toxicologie) (567)
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ROMAND, Stéphanie Anne et al. Characterization of oxycodone in vitro metabolism by human cytochromes P450 and UDP-glucuronosyltransferases. In: Journal of Pharmaceutical and Biomedical Analysis, 2016. https://archive-ouverte.unige.ch/unige:90072

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Deposited on : 2016-12-08

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