Smallwood R H, Mihaly G W, Smallwood R A, Morgan D J
Victorian College of Pharmacy, Melbourne, Australia.
J Pharm Sci. 1988 Apr;77(4):330-3. doi: 10.1002/jps.2600770410.
The kinetics of hepatic elimination of the high-clearance drug propranolol has been interpreted in a previous study from our laboratory, in which propranolol protein binding was varied, to conform to the venous equilibrium model. In another study by a different group, in which perfusate flow was varied, propranolol kinetics was interpreted to conform to the sinusoidal model. In the present study, we investigated the possibility that this discrepancy is due to the use of the two different discriminants, flow and protein binding, in the two studies. In eight livers, perfused in a recirculating design, steady-state elimination of propranolol (infused at a rate of 22.8 micrograms/min) was examined at perfusate flow rates of 16 and 32 mL/min. Hepatic outflow concentration was independent of perfusate flow rate, while the logarithmic average concentration was significantly lower at the higher flow. These data conform to the venous equilibrium model and are not consistent with the sinusoidal model. This shows that the outcome of these modeling experiments does not depend on the experimental approach used, and reaffirms that the venous equilibrium model is appropriate for propranolol under the conditions studied.
在我们实验室之前的一项研究中，对高清除率药物普萘洛尔的肝脏消除动力学进行了解释，该研究中普萘洛尔的蛋白结合情况有所变化，以符合静脉平衡模型。在另一组不同人员进行的研究中，灌注液流量有所变化，普萘洛尔动力学被解释为符合正弦模型。在本研究中，我们调查了这种差异是否是由于两项研究中使用了两种不同的判别因素，即流量和蛋白结合。在八个采用循环设计灌注的肝脏中，在灌注液流速为16和32 mL/min的情况下，检测了普萘洛尔（以22.8微克/分钟的速率输注）的稳态消除情况。肝脏流出浓度与灌注液流速无关，而对数平均浓度在较高流速时显著降低。这些数据符合静脉平衡模型，与正弦模型不一致。这表明这些建模实验的结果并不取决于所使用的实验方法，并重申在研究条件下静脉平衡模型适用于普萘洛尔。
