Pharmacokinetic analysis of disposition of biologically active peptide in the body.

在体外分离细胞系统、灌流器官系统和体内条件下，分析了具有生物活性的多肽激素--β-内啡肽(EP)和表皮生长因子(EGF)的药代动力学。血浆消失曲线和体内碘标记EP的组织摄取动力学分析揭示了多肽在大鼠肺和肝脏中的特异性结合。还对人EGF在大鼠体内的组织分布进行了动力学分析，结果如下：1)肝脏、肾脏和小肠对EGF的摄取呈现明显的饱和状态，这可能代表了受体依赖的摄取机制。2)肝脏对EGF的摄取速度较快，摄取速度受肝脏血浆流量的限制。3)在整个动物体内，EGF从循环中清除的大部分是由肝脏清除造成的。然后，我们用多指示剂稀释法(肝脏灌注法)分析了EGF对肝脏的处理，得到了代表EGF与肝细胞表面受体相互作用的参数。将得到的参数与用离体肝细胞测定的参数进行了比较，结果表明，只有开启速率常数(K&lt；on&gt；)随实验系统的不同而不同。可能存在于肝脏间质间隙的未搅拌水层可能是造成这种差异的原因。最后，基于包含所获得的动力学参数的生理药动学模型，对EGF血浆浓度和肝脏表面受体的时间分布进行了模拟，并指出了肝脏受体下调对其整体动力学的重要性。

Pharmacokinetics of biologically active popypeptide hormones, beta-endorphine(EP) and epidermal growth factor(EGF) have been analyzed using in vitro isolated cell system, perfused organ system and in vivo condition.Kinetio analysis of the plasma disappearance curve and tissue uptake of iodine labeled EP in vivo has revealed the specific binding of the peptide in the lung and liver of the rats.Kinetic analysis of the tissue distribution of human EGF in rats was also performed in vivo, and the following results were obatained. 1)The uptake of EGF by the liver, kidney and small intestine showed clear saturation, which may represent the receptor-dependent uptake mechanism. 2)The hepatic uptake of EGF at low dose was so rapid that the uptake rate is limited by the hepatic plasma flow rate. 3)Inthe whole animal, the bulk of the removal of EGF from the circulation was accounted for by the hepatic clearance. We then analyzed the hepatic handling of EGF by the multiple indicator dilution method ( a liver perfusion method), and obtained the parameters representing the interaction of EGF with the liver cell surface receptors. Comparison of the parameters thus obtained with those determined using isolated hepatocytes has shown that only the on-rate constant(K_<on>) was different depending on the experimental system. Unstirred water layer which may exsist in the interstitial space of the liver could be a cause for this discrepancy. Finally, based on a physiological pharmacokinetic model which incorporated thus obtained kinetic parameters, simulations of the time profiles of plasma concentrations of EGF and the surface receptors of the liver were carried out, and the importance of down-regulation of hepatic receptors to its overall kinetics has been brought out.