S(+)盐酸氯胺酮对大鼠肝微粒体细胞色素P450同工酶的影响

Effect of S(+)-Ketamine on Liver Microsomal Cytochrome P450 Isozymes in Rats

目的研究S(+)盐酸氯胺酮对大鼠肝微粒体细胞色素P450(CYP450)6种主要同工酶的诱导或抑制作用。方法应用HPLC-UV测定CYP450 6种主要同工酶的特异性探针底物右美沙芬(CYP2D)、双氯酚酸钠(CYP2C6)、奥美拉唑(CYP2C)、氨苯砜(CYP3A)、非那西丁(CYP1A2)和氯唑沙宗(CYP2E1)的代谢速率。大鼠iv给予S(+)盐酸氯胺酮25 mg.kg-1.d-1,连续给药7 d,评价药物对大鼠肝微粒体CYP450主要同工酶的诱导或抑制作用。结果S(+)盐酸氯胺酮50μmol.L-1时可明显抑制大鼠肝脏CYP2C,2C6和3A,分别为对照组的61.4%,45.8%和31.3%,其中以对CYP2C的抑制作用最为明显。S(+)盐酸氯胺酮1和10μmol.L-1对CYP450同工酶无明显影响,仅10μmol.L-1S(+)盐酸氯胺酮对CYP2C有轻度抑制作用。S(+)盐酸氯胺酮iv给药7 d后,对大鼠肝微粒体CYP1A2和CYP2C有不同程度的诱导作用,分别诱导137.5%和117.6%,对CYP2E1,3A,2D,2C6无明显影响。结论S(+)盐酸氯胺酮50μmol.L-1时可明显抑制肝脏CYP2C,2C6和3A,连续给药7 d后可诱导CYP1A2和CYP2C,提示S(+)盐酸氯胺酮与经上述同工酶代谢的药物联合应用时,应注意药物-药物相互作用的可能性。

OBJECTIVE To determine the inhibitory or inductive effect of S（ ＋ ）-ketamine on liver microsomal CYP450 isozymes in rats. METHODS Rats were given S （ ＋ ）-ketamine once daily intravenously for seven days. The liver microsomes was prepared for the determination of the metabolic rates of six probe drugs to reflect the activity of liver microsamal CYP450 isozymes by HPLC-UV method. RESULTS The metabolic rates of omeprazole, diclofenac and dapsone were reduced by 61.4%, 45.8% , 31.3% in liver microsomes incubated with 50 μmol·L^-1 S（ ＋ ）-ketamine respectively in vitro, while 1 and 10 μmol·L^-1 S（ ＋ ）-ketamine had no effect on the metabolic rates of other probe drugs except omeprazole was slightly reduced. Moreover, the metabolic rate of phenacetine and omeprazole were increased by 137.5% and 117.6% in rats pretreated with S （ ＋ ）-ketamine. No significant changes on the metabolic rates of chlorzoxazone, dapsone, dextromethorphan and diclofenac were found after multiple administrations of S（ ＋ ）-ketamine. CONCLUSION S（ ＋ ）-ketamine at 50 μmol·L^-1 has inhibitory effect on rat liver microsomal CYP2C, 2C6 and 3A. The activity of CYP1A2 and 2C were induced slightly following multiple administrations of S （ ＋ ）-ketamine. The inhibitory effects of S（ ＋ ）- ketamine on CYP450 isozymes are of a potential for drug-drug interaction when being co-administered with other drugs that were substrates of related CYP450s.