Effect of sodium ozagrel on the activity of rat CYP2D6
- 作者：Hong Wu ; Weijiang Yu ; Lijun Huang ; Jing Wang ; Xiaobo Tang ; Wei Yang ; Yan Liu ; Huiyan Yu ; Daling Zhu
- 关键词：Ozagrel ; CYP2D6 ; Microsome ; HPLC ; Dextromethorphan
- 刊名：European Journal of Pharmacology
- 出版年：2007
- 期刊代码：24_00142999
- 类别：neu
- 出版时间：14 November 2007
- 卷：573
- 期：1-3
- 页码：55-59
- 文件大小：253 K
摘要
The aim of the study was to investigate the influence of sodium ozagrel on CYP2D6 (cytochromeP450 2D6) activity. The studies were performed with rat urine and liver microsomes and chemical inhibitors. The metabolism of dextromethorphan (dextrophan/dextromethorphan, dextrophan is a metabolite of dextromethorphan) and phenacetin (paracetamol/phenacetin, paracetamol is a metabolites of phenacetin) was used as probe to measure CYP2D6 and CYP1A2 (cytochromeP450 1A2) activity, respectively, determined by high-performance liquid chromatography (HPLC). The results showed that the metabolism of dextrophan/dextromethorphan in the sodium ozagrel-treated group (37 mg/kg) was higher than that of the control (P < 0.05/6) in both in vivo and in vitro studies (r = 0.9811). The rate of dextromethorphan metabolism was inhibited by sodium ozagrel and cimetidine in rat liver microsomes prepared from sodium ozagrel-treated rats and control rats group (sodium ozagrel IC50 = 26.5 μM, cimetidine IC50 = 86.3 μM in sodium ozagrel-treated group; sodium ozagrel IC50 = 13.9 μM, cimetidine IC50 = 24.8 μM in control group). The inhibitory effect of sodium ozagrel on CYP2D6 activity was noncompetitive with dextromethorphan with a Ki of 324.94 μM. Kinetic parameters of the reactions were established by using Lineweaver–Burk with Km = 0.67 mM and Vmax = 2.13 pm/min/mg protein for the sodium ozagrel-treated group and Km = 0.29 mM, and Vmax = 0.91 pm/min/mg protein for the control group, respectively. The expression of CYP2D6 protein in the treated group was higher than that of the control group, as determined by Western blotting. The activity and expression of CYP1A2 did not show obvious differences in the control group and sodium ozagrel treated group. In conclusion, sodium ozagrel metabolism in rats is mediated primarily through CYP2D6, and sodium ozagrel can induce CYP2D6 activity.