Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, NY 14260, USA.
J Pharmacokinet Pharmacodyn. 2011 Jun;38(3):293-316. doi: 10.1007/s10928-011-9194-4. Epub 2011 Mar 11.
Influences of methylprednisolone (MPL) and food consumption on body weight (BW), and the effects of MPL on glycemic control including food consumption and the dynamic interactions among glucose, insulin, and free fatty acids (FFA) were evaluated in normal male Wistar rats. Six groups of animals received either saline or MPL via subcutaneous infusions at the rate of 0.03, 0.1, 0.2, 0.3 and 0.4 mg/kg/h for different treatment periods. BW and food consumption were measured twice a week. Plasma concentrations of MPL and corticosterone (CST) were determined at animal sacrifice. Plasma glucose, insulin, and FFA were measured at various times after infusion. Plasma MPL concentrations were simulated by a two-compartment model and used as the driving force in the pharmacodynamic (PD) analysis. All data were modeled using ADAPT 5. The MPL treatments caused reduction of food consumption and body weights in all dosing groups. The steroid also caused changes in plasma glucose, insulin, and FFA concentrations. Hyperinsulinemia was achieved rapidly at the first sampling time of 6 h; significant elevations of FFA were observed in all drug treatment groups; whereas only modest increases in plasma glucose were observed in the low dosing groups (0.03 and 0.1 mg/kg/h). Body weight changes were modeled by dual actions of MPL: inhibition of food consumption and stimulation of weight loss, with food consumption accounting for the input of energy for body weight. Dynamic models of glucose and insulin feedback interactions were extended to capture the major metabolic effects of FFA: stimulation of insulin secretion and inhibition of insulin-stimulated glucose utilization. These models of body weight and glucose regulation adequately captured the experimental data and reflect significant physiological interactions among glucose, insulin, and FFA. These mechanism-based PD models provide further insights into the multi-factor control of this essential metabolic system.
在正常雄性 Wistar 大鼠中，评估了甲基强的松龙 (MPL) 和食物消耗对体重 (BW) 的影响，以及 MPL 对血糖控制的影响，包括食物消耗以及葡萄糖、胰岛素和游离脂肪酸 (FFA) 之间的动态相互作用。六组动物分别接受 0.03、0.1、0.2、0.3 和 0.4mg/kg/h 的不同治疗时间的皮下输注生理盐水或 MPL。每周测量两次 BW 和食物消耗。在动物处死时测定血浆 MPL 和皮质酮 (CST) 浓度。在输注后不同时间测量血浆葡萄糖、胰岛素和 FFA。通过两室模型模拟血浆 MPL 浓度，并将其用作药效学 (PD) 分析的驱动力。使用 ADAPT 5 对所有数据进行建模。MPL 处理导致所有剂量组的食物消耗和体重减少。该类固醇还导致血浆葡萄糖、胰岛素和 FFA 浓度发生变化。在第一次采样时间 6 h 时迅速出现高胰岛素血症；所有药物治疗组均观察到 FFA 的显著升高；而仅在低剂量组（0.03 和 0.1mg/kg/h）观察到血浆葡萄糖的适度增加。体重变化通过 MPL 的双重作用进行建模：抑制食物消耗和刺激体重减轻，食物消耗为体重提供能量输入。葡萄糖和胰岛素反馈相互作用的动态模型扩展到捕获 FFA 的主要代谢作用：刺激胰岛素分泌和抑制胰岛素刺激的葡萄糖利用。这些体重和葡萄糖调节模型充分捕获了实验数据，并反映了葡萄糖、胰岛素和 FFA 之间的重要生理相互作用。这些基于机制的 PD 模型为进一步深入了解这个重要代谢系统的多因素控制提供了依据。
