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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 determine the changes of 6 cytochrome P450 (CYP450) subtypes in reserpine-induced acute depression rats by using Cocktail probe method and to explore the pathogenesis of depression from the perspective of drug metabolism. Methods: The reserpine-induced acute depression model was established. The rats were randomly divided into blank group (group A), model group (group C) and western venlafaxine group (group H) After two weeks, the rats in group H were given continuous administration for 2 weeks. Rats in groups A and C were given clean water for 2 weeks. On day 21, reserpine injection (4 mg · kg -1) The volume of normal saline, fasting on the 22nd day can not help but water for 12 hours. On the 23rd day, the rats in each group were given intragastric administration of 10 mg · kg ~ (-1) mixed probe drugs. Theophylline, chlorzoxazone, tolbutamide, dextromethorphan, omeprazole and midazolam were selected as probe substrates for CYP1A2, CYP2C6, CYP2D1, CYP2D2, CYP2E1 and CYP3A2 in rats. LC- The concentration of six kinds of mixed probes in rats were determined by MS / MS, and the pharmacokinetic parameters were calculated. Results: Tolbutamide in the model rats significantly increased in vivo and the metabolism was slowed down. The concentration of midazolam in rats was significantly reduced and the metabolism was accelerated. After giving anti-depression venlafaxine, theophylline, chlorzoxazone and midazolam in rats significantly increased in concentration, slow metabolism. CONCLUSIONS: Reserpine-induced acute depression model has a moderately strong inhibition of CYP2D1 and CYP2D2 in rats and a moderately strong induction of CYP3A2. After venlafaxine administration, CYP1A2, CYP2C6, CYP2E1 and CYP3A2 are moderately Strong inhibitory effect.