کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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5137942 | 1494591 | 2017 | 9 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: Characterization of oxycodone in vitro metabolism by human cytochromes P450 and UDP-glucuronosyltransferases Characterization of oxycodone in vitro metabolism by human cytochromes P450 and UDP-glucuronosyltransferases](/preview/png/5137942.png)
- Kinetic parameters of oxymorphone and noroxycodone production by HLM were determined.
- UGTs 2B4 and 2B7 were involved in oxycodone metabolism.
- In vitro inhibitory effect of oxycodone were assessed using two CYP and UGT cocktail approaches.
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 1.46 μL/min/mg and 0.35 μL/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 ± 153 μM, Vmax = 344 ± 20 peak area/min/mg) and to a lesser extent by UGT2B4 (Km = 2454 ± 497 μM, 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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Journal: Journal of Pharmaceutical and Biomedical Analysis - Volume 144, 10 September 2017, Pages 129-137