Romand Stéphanie, Spaggiari Dany, Marsousi Niloufar, Samer Caroline, Desmeules Jules, Daali Youssef, Rudaz Serge
School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Rue Michel Servet 1, 1211 Geneva 4, Switzerland.
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.
J Pharm Biomed Anal. 2017 Sep 10;144:129-137. doi: 10.1016/j.jpba.2016.09.024. Epub 2016 Sep 26.
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 (K=762±153μM, V=344±20 peak area/min/mg) and to a lesser extent by UGT2B4 (K=2454±497μM, V=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.
在体外评估了羟考酮通过细胞色素P450（CYP）和尿苷二磷酸葡萄糖醛酸基转移酶（UGT）的肝脏代谢，它们分别是I相和II相的主要代谢酶。人肝微粒体（HLM）中CYP3A4/5介导的N-去甲基化和CYP2D6介导的O-去甲基化均符合米氏动力学，内在清除率分别为1.46μL/分钟/毫克和0.35μL/分钟/毫克。尽管去甲羟考酮和羟吗啡酮是羟考酮消除的主要贡献者，但使用体外I相代谢模拟的体内总清除率被低估了。首次使用HLM、重组酶和选择性抑制剂深入研究了UGT对羟考酮的代谢。羟考酮葡萄糖醛酸苷主要由UGT2B7产生（K = 762±153μM，V = 344±20峰面积/分钟/毫克），其次由UGT2B4产生（K = 2454±497μM，V = 201±19峰面积/分钟/毫克）。最后，使用两种CYP和UGT鸡尾酒方法评估了药物-药物相互作用的动力学。HLM与I相和II相药物探针的孵育表明，羟考酮主要降低了CYP2D6、CYP3A4/5、UGT1A3、UGT1A6和UGT2B亚家族的体外活性，对UGT2B7有重要影响。
