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Effects of glucocorticoids on pharmacokinetics and pharmacodynamics of midazolam in rats.

机译：糖皮质激素对咪达唑仑在大鼠体内的药代动力学和药效学的影响。

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摘要

We investigated the effect of dexamethasone (80 mg/kg per day for 2 days) and prednisolone (600 mg/kg per day for 2 days, equivalent to dexamethasone for glucocorticoid (GC) potency) on both pharmacokinetics and pharmacodynamics of midazolam (MDZ), a substrate for cytochrome P450 (CYP) 3A, in 8-week-old male Sprague-Dawley rats. Animals received a single injection of MDZ (pharmacokinetic study, 10 mg/kg; pharmacodynamic study, 55.5 mg/kg) in the tail vein 24 h after the last dose of GC or placebo. The elimination half-life (t(1/2)) and the area under the concentration-time curve of MDZ were significantly reduced by pretreatment with dexamethasone to 58.9% and 44.7% of the control value, respectively, and the clearance of MDZ was significantly increased by dexamethasone. Similar changes observed by prednisolone pretreatment did not reach significance. The t(1/2) of the dexamethasone pretreatment group (14.4+/-0.7 min) was significantly shorter than that of the prednisolone group (20.9+/-1.5 min). The amount of CYP3A2 protein and the activity of erythromycin N-demethylase were significantly increased by dexamethasone and prednisolone pretreatments, but dexamethasone showed a greater effect than prednisolone. Sleeping time was significantly shortened by dexamethasone and prednisolone pretreatment to 38.7% and 57.1% of control value, respectively. The current study demonstrates that the anesthetic effect of MDZ would be reduced in patients treated with dexamethasone or prednisolone, and that the CYP3A induction was greater by dexamethasone than by prednisolone, implying that the potency of CYP3A induction may differ among GCs even when GC activity is the same.
机译：我们研究了地塞米松（每天80 mg / kg，每天2天）和泼尼松龙（每天600 mg / kg，每天2天，相当于地塞米松的糖皮质激素（GC）效力）对咪达唑仑（MDZ）药代动力学和药效学的影响是8周大的雄性Sprague-Dawley大鼠中细胞色素P450（CYP）3A的底物。在最后一次注射GC或安慰剂后24小时，动物在尾静脉单次注射MDZ（药代动力学研究，10 mg / kg;药效学研究，55.5 mg / kg）。地塞米松预处理显着降低了MDZ的消除半衰期（t（1/2））和浓度-时间曲线下的面积，分别为对照值的58.9％和44.7％，MDZ的清除率为地塞米松明显增加。泼尼松龙预处理所观察到的类似变化没有显着意义。地塞米松预处理组的t（1/2）（14.4 +/- 0.7分钟）显着短于泼尼松龙组（20.9 +/- 1.5分钟）。地塞米松和泼尼松龙预处理可显着增加CYP3A2蛋白的含量和红霉素N-去甲基酶的活性，但地塞米松的作用明显大于泼尼松龙。地塞米松和泼尼松龙预处理可将睡眠时间分别显着缩短至对照组的38.7％和57.1％。目前的研究表明，在地塞米松或泼尼松龙治疗的患者中，MDZ的麻醉作用会降低，地塞米松比强的松龙对CYP3A的诱导作用更大，这意味着即使GC活性为相同。

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