Pharmacodynamics of Cibenzoline-Induced Hypoglycemia in Rats
Pharmacodynamics of Cibenzoline-Induced Hypoglycemia in Rats
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DOI：
10.2133/dmpk.dmpk-10-rg-127
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发表时间：
2011-01-01
影响因子：
2.1
通讯作者：
Yasuhara, Masato
中科院分区：
文献类型：
--
作者：
Takahashi, Yutaka;Ishiwata, Yasuyoshi;Yasuhara, Masato
低血糖是抗抑郁药西苯唑啉（CBZ）的严重不良反应之一。为了阐明CBZ引起的低血糖的药效学，CBZ以5、10或20 mg/kg的剂量静脉给予清醒大鼠，并定期收集血清样品以测定CBZ、胰岛素和葡萄糖的浓度。CBZ在大鼠体内的药代动力学呈非线性，符合二室米氏消除动力学模型。CBZ诱导血清胰岛素浓度迅速升高。随着CBZ剂量的增加，发生了更大的降血糖作用。应用间接反应模型解释CBZ诱导的胰岛素分泌增加和随后的血清葡萄糖降低。CBZ对胰岛素分泌的刺激作用与血药浓度呈线性关系。血清胰岛素浓度与其对血糖清除的促进作用呈非线性关系。所建立的药动学和药效学模型可描述静脉注射CBZ后血药浓度、胰岛素和葡萄糖浓度的时程变化。这种方法将有助于识别与CBZ诱导的低血糖相关的可变因素。
Hypoglycemia is one of the serious adverse effects induced by cibenzoline (CBZ), an antiarrhythmic agent. In order to clarify the pharmacodynamics of CBZ-induced hypoglycemia, CBZ was administered intravenously to conscious rats at a dose of 5, 10 or 20 mg/kg and serum samples were collected periodically to determine the concentrations of CBZ, insulin and glucose. The pharmacokinetics of CBZ showed nonlinear characteristics and could be described by a two-compartment model with Michaelis-Menten elimination kinetics. CBZ induced a rapid increase in the serum concentration of insulin. As the CBZ dose was increased, a greater hypoglycemic effect occurred. The indirect response model was applied to account for the CBZ-induced increase in insulin secretion and the subsequent decrease in serum glucose. A linear relationship was assumed between the serum concentration of CBZ and its stimulating effect on insulin secretion. A nonlinear relationship was assumed between the serum concentration of insulin and its stimulating effect on the elimination of serum glucose. The time courses of serum concentrations of CBZ, insulin and glucose after intravenous injection of CBZ could be described by the pharmacokinetic and pharmacodynamic model developed. This approach will be useful for the identification of variable factors related to CBZ-induced hypoglycemia.