Vestergaard Bill, Appa Rupa S, Lykkesfeldt Jens, Agersø Henrik
Biopharmaceuticals Research Unit, Novo Nordisk A/S, Måløv, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
Biopharmaceuticals Research Unit, Novo Nordisk A/S, Måløv, Denmark.
Thromb Res. 2014 Jun;133(6):1124-9. doi: 10.1016/j.thromres.2014.03.034. Epub 2014 Mar 25.
Previous distribution and histological studies have indicated that the kidneys and renal proximal tubular cells play a role in clearance of rFVIIa. However, the relative importance of the kidneys in clearance of rFVIIa has not previously been addressed. The objective of the present study was to evaluate the importance of the kidneys in the clearance process of rFVIIa after iv administration to rats using a nephrectomy model.
A nephrectomized rat model was established and validated using inulin, a compound primarily cleared by the kidneys, as a test substance and several physiological parameters were monitored to ensure viability and robustness of the model. The model was then used for pharmacokinetic evaluation of renal clearance of rFVIIa. The pharmacokinetic parameters for rFVIIa were evaluated both by use of standard non-compartmental methods and by use of mixed effects methods, where a pharmacokinetic model was used to simultaneously model all data from healthy, sham operated, and nephrectomized rats.
Nephrectomized animals showed stable rectal temperature, SpO2 and pulse and as expected, clearance of inulin was essentially abolished compared to control animals (p<0.001). For rFVIIa, nephrectomy resulted in a clearance and terminal half-life of 34mL/h/kg and 2.8h compared to 68mL/h/kg and1.9h in rats exposed to sham surgery (p<0.0001 for both parameters).
The present data show that about 50% of the total clearance of rFVIIa from circulation in rats under isoflurane anaesthesia is due to renal clearance.
先前的分布和组织学研究表明，肾脏和肾近端小管细胞在重组活化凝血因子VII（rFVIIa）的清除过程中发挥作用。然而，肾脏在rFVIIa清除中的相对重要性此前尚未得到探讨。本研究的目的是使用肾切除模型评估肾脏在大鼠静脉注射rFVIIa后的清除过程中的重要性。
建立并验证了肾切除大鼠模型，使用菊粉（一种主要由肾脏清除的化合物）作为测试物质，并监测了几个生理参数以确保模型的生存能力和稳定性。然后将该模型用于rFVIIa肾清除的药代动力学评估。通过使用标准的非房室方法和混合效应方法评估rFVIIa的药代动力学参数，其中使用药代动力学模型同时对来自健康、假手术和肾切除大鼠的所有数据进行建模。
肾切除动物的直肠温度、血氧饱和度（SpO2）和脉搏保持稳定，正如预期的那样，与对照动物相比，菊粉的清除率基本消失（p<0.001）。对于rFVIIa，肾切除导致清除率和末端半衰期分别为34mL/h/kg和2.8小时，而假手术大鼠分别为68mL/h/kg和1.9小时（两个参数的p均<0.0001）。
目前的数据表明，在异氟烷麻醉下，大鼠体内rFVIIa从循环中的总清除率约50%归因于肾清除。
