Department of Pharmaceutical Sciences, State University of New York, Buffalo, NY, USA.
J Pharmacol Exp Ther. 2011 Mar;336(3):881-90. doi: 10.1124/jpet.110.175752. Epub 2010 Dec 14.
The pharmacokinetics (PK) and pharmacodynamics (PD) of exendin-4 were studied in type 2 diabetic Goto-Kakizaki rats after single doses at 0.5, 1, 5, or 10 μg/kg by intravenous administration and 5 μg/kg by subcutaneous administration. Plasma exendin-4, glucose, and insulin concentrations were determined. A target-mediated drug disposition model was used to characterize the PK of exendin-4. Glucose turnover was described by an indirect response model, with insulin stimulating glucose disposition. Insulin turnover was characterized by an indirect response model with a precursor compartment. After intravenous doses, exendin-4 rapidly disappeared from the circulation, whereas it exhibited rapid absorption (T(max) = 15-20 min) and incomplete bioavailability (F = 0.51) after the subcutaneous dose. Exendin-4 increased insulin release at 2 to 5 min with capacity S(max) = 6.91 and sensitivity SC₅₀ = 1.29 nM, followed by a rebound at 10 to 15 min and a slow return to the baseline. Glucose initially declined because of enhanced insulin secretion, and then gradually increased because of the activation of the neural system by exendin-4. The hyperglycemic action was modeled with increased hepatic glucose production with a linear factor S(RC) = 0.112 1/nM. The mechanistic PK/PD model satisfactorily described the disposition and effects of exendin-4 on glucose and insulin homeostasis in type 2 diabetic rats.
在单次静脉给予 0.5、1、5 或 10μg/kg 和皮下给予 5μg/kg 后的 2 型糖尿病 Goto-Kakizaki 大鼠中，研究了 exendin-4 的药代动力学（PK）和药效动力学（PD）。测定了血浆 exendin-4、葡萄糖和胰岛素浓度。使用靶介导的药物处置模型来描述 exendin-4 的 PK。葡萄糖周转通过间接反应模型进行描述，胰岛素刺激葡萄糖处置。胰岛素周转通过具有前体隔室的间接反应模型进行特征化。静脉给药后，exendin-4 迅速从循环中消失，而皮下给药后则迅速吸收（T(max)=15-20min）且生物利用度不完全（F=0.51）。exendin-4 在 2 至 5min 时增加胰岛素释放，能力 S(max)=6.91，灵敏度 SC₅₀=1.29nM，随后在 10 至 15min 时出现反弹，然后缓慢恢复基线。葡萄糖最初因胰岛素分泌增强而下降，然后逐渐因 exendin-4 激活神经系统而增加。高血糖作用通过具有线性因子 S(RC)=0.112 1/nM 的肝葡萄糖生成增加来建模。该机制 PK/PD 模型令人满意地描述了 exendin-4 在 2 型糖尿病大鼠葡萄糖和胰岛素稳态中的处置和作用。
