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目的考察细胞色素P450(CYP450)亚型酶在大鼠肝内氯胺酮N-去甲基代谢中的作用。方法选择CYP450亚型酶的专属性诱导剂β-萘黄酮、苯巴比妥钠、利福平、异烟肼和地塞米松,腹腔给药对实验大鼠肝微粒体进行诱导;考察经诱导后的各组肝微粒体氯胺酮N-去甲基代谢速率。选择CYP450专属性抑制剂α-萘黄酮、磺胺甲恶唑和奥美拉唑、硫酸奎宁和酮康唑,对大鼠空白肝微粒体进行体外抑制;考察各组氯胺酮N-去甲基代谢速率。上述结果分别与对照组进行比较。结果经苯巴比妥钠和地塞米松诱导,氯胺酮代谢速率有显著性变化(P<0.05～0.001),去甲氯胺酮的生成速率分别是对照组的2.3～4.6倍和1.4～1.9倍,其余诱导剂对氯胺酮代谢无影响。经酮康唑作用,氯胺酮的代谢产生显著抑制(P<0.001),N-去甲基活性为对照组的47.20%～28.97%,其余抑制剂对氯胺酮代谢无影响。结论CYP450亚型酶中CYP2B和CYP3A参与了氯胺酮N-去甲基代谢,氯胺酮可能在体内与上述酶底物发生相互作用。
Objective To investigate the role of cytochrome P450 (CYP450) isoform in ketamine N-demethylation in rat liver. Methods Specific inhibitors of CYP450-type enzymes, β-naphthoflavone, phenobarbital, rifampicin, isoniazid and dexamethasone, were administered intraperitoneally to induce liver microsomes in rats. After each group of liver microsomes ketamine N-to-methyl metabolism rate. Select CYP450 inhibitors α-naphthoflavone, sulfamethoxazole and omeprazole, quinine sulfate and ketoconazole in vitro inhibition of blank liver microsomes; study ketamine N-demethylation rate. The above results were compared with the control group. Results The metabolic rate of ketamine significantly decreased after phenobarbital sodium and dexamethasone treatment (P <0.05-0.001). The rates of demethylation of ketamine were 2.3- to 4.6-fold and 1.4-1.9-fold higher than those of the control group, respectively Inducers have no effect on ketamine metabolism. After ketoconazole treatment, the metabolism of ketamine was significantly inhibited (P <0.001). The N-demethylation activity was 47.20% -28.97% of the control group. The rest of the inhibitors had no effect on ketamine metabolism. Conclusion CYP2B and CYP3A in CYP450 is involved in ketamine N-demethylation, and ketamine may interact with the above substrate in vivo.