Miyauchi S, Sugiyama Y, Iga T, Hanano M
Faculty of Pharmaceutical Sciences, University of Tokyo, Japan.
J Pharm Sci. 1988 Aug;77(8):688-92. doi: 10.1002/jps.2600770809.
The hepatic transports of 4-methylumbelliferone (4-MU) and its conjugative metabolites, the glucuronide (4-MUG) and sulfate (4-MUS), were investigated in rats with various methods. The extraction ratio (E) was estimated with the multiple indicator dilution (MID) method using isolated perfused rat liver. The values of E for 4-MUG and 4-MUS were much lower (less than 0.2) than that for the parent compound, 4-MU (0.89). In addition, we examined the simulation of the outflow curves of conjugates based on the "distributed" model in which we varied the permeability between the blood and hepatocytes. When the permeability was much smaller relative to the hepatic blood flow, the simulated curve was superimposed on the dilution curve. These results suggest that the influx permeabilities of these conjugates are so low that little extraction occurs during the passage through the liver. Measuring the unidirectional uptake of these conjugates into the liver with the in vitro centrifugal filtration method using isolated hepatocytes, we determined the influx permeabilities (PSinf(total] for the total ligands. The value of PSinf(total) determined with the in vitro method was extrapolated to that per gram of liver, assuming 1 g of liver has 1.3 X 10(8) cells. The values of PSinf(total) for 4-MU, 4-MUG, and 4-MUS were 4.8, 0.06, and 0.11 mL/min/g liver, respectively. Thus, the influx permeabilities for 4-MUG and 4-MUS were much smaller than the hepatic blood flow (1.6 mL/min/g liver), confirming the results of MID method.
采用多种方法对大鼠体内4-甲基伞形酮（4-MU）及其结合代谢产物葡萄糖醛酸苷（4-MUG）和硫酸酯（4-MUS）的肝脏转运进行了研究。使用离体灌注大鼠肝脏，通过多指示剂稀释（MID）法估算提取率（E）。4-MUG和4-MUS的E值（小于0.2）远低于母体化合物4-MU的E值（0.89）。此外，我们基于“分布”模型对结合物流出曲线进行了模拟，在该模型中改变了血液与肝细胞之间的通透性。当通透性相对于肝血流量小得多时，模拟曲线与稀释曲线重叠。这些结果表明，这些结合物的流入通透性很低，以至于在通过肝脏的过程中几乎没有提取发生。使用离体肝细胞通过体外离心过滤法测量这些结合物向肝脏的单向摄取，我们确定了总配体的流入通透性（PSinf(total)）。假设1 g肝脏含有1.3×10(8)个细胞，将体外方法测定的PSinf(total)值外推至每克肝脏的值。4-MU、4-MUG和4-MUS的PSinf(total)值分别为4.8、0.06和0.11 mL/min/g肝脏。因此，4-MUG和4-MUS的流入通透性远小于肝血流量（1.6 mL/min/g肝脏），证实了MID法的结果。
