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首页> 外文期刊>Journal of pharmacokinetics and biopharmaceutics >Dose-dependence and repeated-dose studies for receptor/gene-mediated pharmacodynamics of methylprednisolone on glucocorticoid receptor down-regulation and tyrosine aminotransferase induction in rat liver.
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Dose-dependence and repeated-dose studies for receptor/gene-mediated pharmacodynamics of methylprednisolone on glucocorticoid receptor down-regulation and tyrosine aminotransferase induction in rat liver.

机译：受体/基因介导的甲泼尼龙对大鼠肝脏糖皮质激素受体下调和酪氨酸氨基转移酶诱导的药效学的剂量依赖性和重复剂量研究。

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摘要

Dose-dependent and repeated-dose effects of methylprednisolone (MPL) on down-regulation of glucocorticoid receptor messenger RNA (GR mRNA) and GR density, as well as tyrosine aminotransferase (TAT) mRNA and TAT induction by receptor/gene-mediated mechanisms in rat liver were examined. A previously developed pharmacokinetic/pharmacodynamic (PK/PD) model was used to design these studies which sought to challenge the model. Three groups of male adrenalectomized Wistar rats received MPL by i.v. injection: low-dose (10 mg/kg at Time 0), high-dose (50 mg/kg at Time 0), and dual-dose (50 mg/kg at Time 0 and 24 hr). Plasma concentrations of MPL, and hepatic content of free GR, GR mRNA, TAT mRNA, and TAT activity were determined. The P-Pharm program was applied for population analysis of MPL PK revealing low interindividual variation in CL and Vc values (3-14%). Two indirect response models were applied to test two competing hypotheses for GR mRNA dynamics. Indirect Pharmacodynamic Response Model I (Model A) where the complex in the nucleus decreases the transcription rate of GR mRNA better described GR mRNA/GR down-regulation. Levels of TAT mRNA began to increase at 1-2 hr, reached a maximum at 5-6 hr, and declined to the baseline at 12-14 hr after MPL dosing. The induction of TAT activity followed a similar pattern with a delay of about 1-2 hr. The low-dose group had 50-60% of the TAT mRNA and TAT induction compared to the high-dose group. Since the GR density returned to about 70% of the baseline level before the second 50 mg/kg dose at 24 hr, tolerance was found for TAT mRNA/TAT induction where only 50-60% of the initial responses were produced. Our fourth-generation model describes the dose dependence and tolerance effects of TAT mRNA/TAT induction by MPL involving multiple-step signal transduction controlled by the steroid regimen, free GR density, and GR occupancy. This model may provide the foundation for studying other induced proteins or enzymes mediated by the similar receptoruclear events.
机译：甲基强的松龙（MPL）对糖皮质激素受体信使RNA（GR mRNA）和GR密度以及酪氨酸转氨酶（TAT）mRNA和TAT的受体/基因介导机制的下调具有剂量依赖性和重复剂量作用检查大鼠肝脏。使用先前开发的药代动力学/药效学（PK / PD）模型来设计这些试图挑战该模型的研究。三组雄性肾上腺切除的Wistar大鼠通过静脉内注射接受了MPL。注射：小剂量（时间0为10 mg / kg），大剂量（时间0为50 mg / kg）和双剂量（时间0和24小时为50 mg / kg）。测定血浆MPL浓度以及游离GR，GR mRNA，TAT mRNA和TAT活性的肝含量。 P-Pharm程序用于MPL PK的人群分析，揭示了CL和Vc值之间的个体差异低（3-14％）。应用了两个间接响应模型来测试两个相互竞争的关于GR mRNA动态的假设。间接药效学反应模型I（模型A）中的原子核复合物降低了GR mRNA的转录速率，可以更好地描述GR mRNA / GR的下调。在MPL给药后，TAT mRNA的水平在1-2小时开始增加，在5-6小时达到最大值，并在12-14小时降至基线。 TAT活性的诱导遵循相似的模式，延迟约1-2小时。与高剂量组相比，低剂量组的TAT mRNA和TAT诱导率为50-60％。由于在24小时第二次50 mg / kg剂量之前，GR密度恢复到基线水平的约70％，因此发现对TAT mRNA / TAT诱导具有耐受性，其中仅产生50-60％的初始应答。我们的第四代模型描述了MPL诱导TAT mRNA / TAT的剂量依赖性和耐受效应，涉及类固醇方案，游离GR密度和GR占用控制的多步信号转导。该模型可以为研究由相似的受体/核事件介导的其他诱导的蛋白质或酶提供基础。

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