Miyauchi S, Sawada Y, Iga T, Hanano M, Sugiyama Y
Department of Biophysics and Physicochemistry, Faculty of Pharmaceutical Sciences, University of Hokkaido, Sapporo, Japan.
Pharm Res. 1993 Mar;10(3):434-40. doi: 10.1023/a:1018952709120.
The hepatic uptake clearances of 15 ligands with a wide range of permeabilities were determined in rats using two techniques: centrifugal filtration with isolated hepatocytes and the multiple indicator dilution (MID) method with isolated perfused livers. Some of the uptake clearance values were taken from the literature. Uptake clearance values obtained from isolated hepatocytes were extrapolated to that per gram liver (PSinf.cell), assuming that 1 g of liver has 1.3 x 10(8) cells. The values of PSinf.cell varied from approximately 0.1 to 72 (mL/min/g liver). The values of PSinf.cell were similar to those (PSinf.MID) determined by the MID method for ligands with uptake clearances below approximately 1 mL/min/g liver. However, for the ligands with larger uptake clearances, the PSinf.MID values were lower than the PSinf.cell values and appeared to reach an upper limit (approx. 15-20 mL/min/g liver). The PSinf.cell values of 1-propranolol, tetraphenylphosphonium (TPP+), and diazepam were 72, 43, and 22 mL/min/g liver, respectively, whereas their uptake clearances (PSinf.MID) determined by the MID method were 4 to 10 times lower. One of the possible mechanisms for this discrepancy is that an unstirred water layer, which may exist in Disse's space in isolated perfused livers (and probably under in vivo condition), limits the hepatic uptake rate of ligands with extremely high membrane permeabilities.
使用两种技术在大鼠中测定了15种具有广泛通透性的配体的肝脏摄取清除率：采用分离的肝细胞进行离心过滤和采用分离的灌注肝脏进行多指示剂稀释（MID）法。部分摄取清除率值取自文献。假设1 g肝脏含有1.3×10⁸个细胞，将从分离的肝细胞获得的摄取清除率值外推至每克肝脏的值（PSinf.cell）。PSinf.cell值在约0.1至72（mL/min/g肝脏）之间变化。对于摄取清除率低于约1 mL/min/g肝脏的配体而言，PSinf.cell值与通过MID法测定的值（PSinf.MID）相似。然而，对于摄取清除率较高的配体，PSinf.MID值低于PSinf.cell值，且似乎达到一个上限（约15 - 20 mL/min/g肝脏）。1 - 普萘洛尔、四苯基鏻（TPP⁺）和地西泮的PSinf.cell值分别为72、43和22 mL/min/g肝脏，而通过MID法测定的它们的摄取清除率（PSinf.MID）则低4至10倍。这种差异的一种可能机制是，在分离的灌注肝脏的狄氏间隙中（可能在体内条件下也存在）可能存在的一个未搅动水层，限制了具有极高膜通透性的配体的肝脏摄取速率。
