Meijer D K, Blom A, Weitering J G, Hornsveld R
J Pharmacokinet Biopharm. 1984 Feb;12(1):43-65. doi: 10.1007/BF01063610.
The influence of intracellular and extracellular protein binding on the hepatic storage and biliary elimination of dibromosulfophthalein (DBSP) was studied in isolated perfused rat liver. Under first order kinetic conditions the amount of DBSP in the liver at a given plasma concentration (hepatic storage) was determined by extracellular binding to albumin and intracellular binding to the cytosolic Y and Z proteins as well as concentrative membrane transport from plasma into the liver. At higher doses, extensive binding of DBSP to intracellular organelles also occurred while liver cytosol/plasma concentration gradients of unbound DBSP were much lower. Hepatic storage increased with decreasing albumin concentration in the perfusate of isolated perfused rat livers. However, it was shown that this parameter is dose-dependent, and errors can be introduced in its calculation if nonlinearity of sinusoidal and canalicular transport processes as well as nonlinear protein binding are not taken into account. The influence of another organic anion, indocyanine green (ICG) on the hepatic storage, subcellular distribution, and elimination of DBSP was subsequently studied. At equimolar amounts the presence of ICG resulted in a 50% decrease in hepatic clearance and hepatic distribution volume of DBSP. It was inferred that these changes are due to an inhibition of carrier-mediated transport across the sinusoidal and canalicular membrane and preferential displacement from intracellular binding sites. In contrast DBSP in equimolar amount enhanced the initial disappearance rate and biliary excretion of ICG, probably due to increasing its free fraction in plasma. It is concluded that the level and mechanism of interaction of two drugs within the eliminating organ can be characterized by combining clearance studies with data on subcellular and extracellular binding.
在离体灌注大鼠肝脏中研究了细胞内和细胞外蛋白质结合对二溴磺酞钠（DBSP）肝脏储存和胆汁排泄的影响。在一级动力学条件下，给定血浆浓度时肝脏中DBSP的量（肝脏储存）由细胞外与白蛋白的结合、细胞内与胞质Y和Z蛋白的结合以及从血浆到肝脏的浓缩性膜转运决定。在较高剂量时，DBSP也会与细胞内细胞器大量结合，而未结合的DBSP的肝细胞溶质/血浆浓度梯度则低得多。在离体灌注大鼠肝脏的灌注液中，肝脏储存量随白蛋白浓度降低而增加。然而，研究表明该参数是剂量依赖性的，如果不考虑窦状隙和胆小管转运过程的非线性以及非线性蛋白质结合，在计算中可能会引入误差。随后研究了另一种有机阴离子吲哚菁绿（ICG）对DBSP肝脏储存、亚细胞分布和排泄的影响。在等摩尔量时，ICG的存在导致DBSP的肝脏清除率和肝脏分布容积降低50%。据推测，这些变化是由于载体介导的跨窦状隙和胆小管膜转运受到抑制以及从细胞内结合位点的优先置换。相反，等摩尔量的DBSP提高了ICG的初始消失率和胆汁排泄，可能是由于增加了其在血浆中的游离分数。结论是，通过将清除率研究与亚细胞和细胞外结合数据相结合，可以表征两种药物在消除器官内相互作用的水平和机制。
