利血平诱导的急性抑郁模型大鼠体内CYP450亚酶的活性变化
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摘要
目的:运用Cocktail探针法测定利血平诱导的急性抑郁模型大鼠体内6种细胞色素P450(CYP450)亚酶活性变化,从药物代谢相互作用的角度探寻抑郁症的发病机制。方法:建立利血平诱导的急性抑郁模型,大鼠随机分为空白组(记为A组),模型组(记为C组)和西药文拉法辛组(记为H组),适应1星期后,H组连续给药2周,A组和C组给予清水2周,第21天C组和H组按4 mg·kg~(-1)腹腔注射利血平注射剂,A组注射等体积生理盐水,第22天禁食不禁水12 h,第23天各组大鼠按10 m L·kg~(-1)灌胃给予混合探针药物。选取茶碱、氯唑沙宗、甲苯磺丁脲、右美沙芬、奥美拉唑以及咪达唑仑作为大鼠CYP1A2,CYP2C6,CYP2D1,CYP2D2,CYP2E1和CYP3A2的探针底物,采用LC-MS/MS测定大鼠体内6种混合探针的血药浓度,计算药动学参数。结果:造模后甲苯磺丁脲在大鼠体内浓度显著升高、代谢减慢;咪达唑仑在大鼠体内浓度显著降低、代谢加快。给予抗抑郁文拉法辛后,茶碱、氯唑沙宗和咪达唑仑在大鼠体内浓度显著升高、代谢减慢。结论:利血平诱导的急性抑郁模型状态对大鼠CYP2D1和CYP2D2有中强抑制作用,对CYP3A2有中强诱导作用;给予文拉法辛后对模型大鼠CYP1A2,CYP2C6,CYP2E1,CYP3A2为中强抑制作用。
Objective: To investigate the activity change of six kinds of cytochrome P450( CYP450)subunit in the acute depression model rats induced by reserpine based on cocktail probe substrates method,in order to explore the pathogenesis of the depression from interaction of drug metabolism. Method: Based on the literatures at home and abroad to establish the acute depression model induced by reserpine,rats were randomly divided into the blank group, the model group and the venlafaxine group. Theophylline, chlorzoxazone,tolbutamide,dextromethorphan, omeprazole and midazolam were selected as probe substrates of CYP1A2,CYP2C6, CYP2D1, CYP2D2, CYP2E1 and CYP3A2 in rats, LC-MS / MS was developed for determining concentrations and pharmacokinetic parameters of six kinds of mixed probe in rats. Result: The concentration of tolbutamide in the model group rats increased significantly with slow metabolism,the concentration of midazolam in rats decreased significantly and metabolism accelerated. After administration of venlafaxine, concentrations of theophylline,chlorzoxazone and midazolam in rats increased significantly with slow metabolism. Conclusion:Acute depression model state induced by reserpine has strong inhibition effect on CYP2D1 and CYP2D2 in rats,and has strong induction on CYP3A2. Venlafaxine has strong inhibition effect on CYP1A2,CYP2C6,CYP2E1 and CYP3A2 in the model rats.
Objective: To investigate the activity change of six kinds of cytochrome P450( CYP450)subunit in the acute depression model rats induced by reserpine based on cocktail probe substrates method,in order to explore the pathogenesis of the depression from interaction of drug metabolism. Method: Based on the literatures at home and abroad to establish the acute depression model induced by reserpine,rats were randomly divided into the blank group, the model group and the venlafaxine group. Theophylline, chlorzoxazone,tolbutamide,dextromethorphan, omeprazole and midazolam were selected as probe substrates of CYP1A2,CYP2C6, CYP2D1, CYP2D2, CYP2E1 and CYP3A2 in rats, LC-MS / MS was developed for determining concentrations and pharmacokinetic parameters of six kinds of mixed probe in rats. Result: The concentration of tolbutamide in the model group rats increased significantly with slow metabolism,the concentration of midazolam in rats decreased significantly and metabolism accelerated. After administration of venlafaxine, concentrations of theophylline,chlorzoxazone and midazolam in rats increased significantly with slow metabolism. Conclusion:Acute depression model state induced by reserpine has strong inhibition effect on CYP2D1 and CYP2D2 in rats,and has strong induction on CYP3A2. Venlafaxine has strong inhibition effect on CYP1A2,CYP2C6,CYP2E1 and CYP3A2 in the model rats.
引文
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[2]宗阳,何书芬,孙冰婷,等.甘草抗抑郁作用机制研究及应用概况[J].中国实验方剂学杂志,2016,22(10):194-198.
[3]臧雨馨,孙冰婷,赵文珠,等.慢性不可预见性温和应激模型大鼠的肝脏药物代谢酶活性变化研究[J].药学学报,2015,50(3):319-325.
[4]宗阳,朱立静,孙冰婷,等.利血平诱导的抑郁模型的研究进展[J].中国药房,2016,27(19):2697-2699.
[5]Breimer D D,Schellens J H.A cocktail strategy to assess in vivo oxidative drug metabolism in humans[J].Trends Pharm Sci,1990,11(6):223-225.
[6]赵文珠,居文政,臧雨馨,等.毛冬青胶囊对大鼠体内细胞色素P450代谢活性的影响[J].药学与临床研究,2015,23(3):217-222.
[7]孙冰婷,张倩,宗阳,等.混合探针法评价白香丹胶囊对大鼠体内CYP450酶活性的影响[J].药学与临床研究,2016,24(1):6-10.
[8]武洁,钟荣玲,王大为,等.HPLC-MS-MS法测定大鼠血浆中6种CYP450探针药物及甘草对CYP450酶活性的影响[J].中国实验方剂学杂志,2014,20(23):110-116.
[9]孙冰婷,居文政,谈恒山.Cocktail法研究CYP450酶活性影响因素的探讨[J].中国医院药学杂志,2015,35(6):558-562.
[10]HUANG S M,Temple R,Throckmorton D C,et al.Drug interaction studies:study design,data analysis,and implications for dosing and labeling[J].Clin Pharmacol Ther,2007,81(2):298-304.
[11]刘佳莉,苑玉和,陈乃宏.抑郁症的治疗研究进展[J].中国药理学通报,2011,27(9):1193-1196.