Stepensky David, Friedman Michael, Raz Itamar, Hoffman Amnon
Department of Pharmaceutics, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem, Israel.
Drug Metab Dispos. 2002 Aug;30(8):861-8. doi: 10.1124/dmd.30.8.861.
Metformin, a commonly used antidiabetic drug, exerts its glucose-lowering effect due to metabolic activities at several sites of action (biophases), including liver, intestine, muscle cells, and adipocytes. The relative contribution of the individual biophases to the overall glucose-lowering effect is not known. Thus, the aims of this investigation were to study the influence of mode of drug administration on the kinetics of glucose-lowering action of metformin in diabetic rats and identify the contribution of different sites of action to the overall response. Streptozotocin diabetic rats received metformin in crossover fashion via intraduodenal, intravenous, and intraportal routes as bolus dose or infusion regimens designed to yield similar pharmacokinetic profiles. Metformin plasma concentrations and blood glucose levels were measured following each mode of administration. Despite the similarity in the concentration-time profiles obtained for different routes of metformin administration, intraduodenal administration produced larger response than intraportal metformin infusion, and lowest response was observed following intravenous administration. This finding indicates that a significant "first-pass" pharmacodynamic effect, which occurs in the presystemic sites of action (liver and the gastrointestinal wall), contributes to the overall glucose-lowering response of metformin. We applied a combined pharmacokinetic-pharmacodynamic modeling approach to study the nature of the first-pass pharmacodynamic effect. The observed data were successfully described by a novel integrated indirect response pharmacokinetic-pharmacodynamic model that revealed a correlation between the temporal metformin concentrations that transit the portal vein and through the gut wall rather than with drug concentrations that accumulated in the liver and the intestinal wall.
二甲双胍是一种常用的抗糖尿病药物，因其在肝脏、肠道、肌肉细胞和脂肪细胞等多个作用部位（生物相）的代谢活动而发挥降血糖作用。各个生物相对总体降血糖作用的相对贡献尚不清楚。因此，本研究的目的是研究给药方式对糖尿病大鼠二甲双胍降血糖作用动力学的影响，并确定不同作用部位对总体反应的贡献。链脲佐菌素诱导的糖尿病大鼠以交叉方式通过十二指肠内、静脉内和门静脉内途径接受二甲双胍，给药方式为推注剂量或输注方案，旨在产生相似的药代动力学特征。在每种给药方式后测量二甲双胍血浆浓度和血糖水平。尽管不同给药途径获得的浓度-时间曲线相似，但十二指肠内给药产生的反应比门静脉内输注二甲双胍更大，静脉内给药后观察到的反应最小。这一发现表明，在体循环前作用部位（肝脏和胃肠道壁）发生的显著“首过”药效学效应有助于二甲双胍的总体降血糖反应。我们应用了一种联合药代动力学-药效学建模方法来研究首过药效学效应的性质。通过一种新型的综合间接反应药代动力学-药效学模型成功地描述了观察到的数据，该模型揭示了通过门静脉和肠道壁转运的二甲双胍浓度随时间的相关性，而不是与在肝脏和肠壁中积累的药物浓度相关。
