Tan E, Lu T, Pang K S
Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Toronto, 19 Russell Street, Toronto, Ontario M5S 2S2, Canada.
J Pharmacol Exp Ther. 2001 Apr;297(1):423-36.
The futile cycling of estrone sulfate (E(1)S) and estrone (E1) was investigated in the recirculating, perfused, rat liver preparation. Although E(1)S was not distributed into bovine erythrocytes, the compound was highly bound to albumin [4% bovine serum albumin (BSA), unbound fraction of 0.03 +/- 0.01]. By contrast, E1 was bound and metabolized to estradiol (E2) by bovine erythrocytes, with metabolic clearances of 0.061 to 0.069 ml/min when normalized to the hematocrit. Due to strong binding of E1 to albumin, BSA (4%) greatly reduced the red cell clearance to a minimum (0.0024 to 0.0031 ml/min/unit of hematocrit). Despite the low unbound fractions of E(1)S (0.027 +/- 0.004) and E1 (0.036 +/- 0.006), clearances of the simultaneously delivered tracers [(3)H]E(1)S and [(14)C]E1 in perfusate (4% BSA and 20% erythrocytes) by the recirculating, perfused rat liver (flow rate of 0.91 +/- 0.1 ml/min/g of liver) were high (0.53 +/- 0.08 and 0.85 +/- 0.2 ml/min/g of liver, respectively). Although low levels of [(3)H]E1 were observed following the tracer [(3)H]E(1)S, both parent and metabolite species displayed similar decay half-lives that were characteristic of compounds undergoing futile cycling. The same decay profile was observed for [(14)C]E(1)S but the half-life of administered [(14)C]E1 was shorter in comparison. A series-compartment liver model that incorporated previously noted heterogeneity in estrone sulfation and glucuronidation activities among periportal and perivenous hepatocytes, and homogeneity in sinusoidal transport and desulfation was used to explain the discrepant half-lives. The model described a high partitioning of E1 in the endoplasmic reticulum and the segregation of estrone sulfation activities in the cytosolic space from the desulfation and glucuronidation activities in the endoplasmic reticulum space.
在大鼠肝脏再循环灌注制备模型中，对硫酸雌酮（E(1)S）和雌酮（E1）的无效循环进行了研究。尽管E(1)S不分布于牛红细胞中，但该化合物与白蛋白高度结合[4%牛血清白蛋白（BSA），未结合部分为0.03±0.01]。相比之下，E1被牛红细胞结合并代谢为雌二醇（E2），以血细胞比容标准化后的代谢清除率为0.061至0.069 ml/min。由于E1与白蛋白的强结合，4%的BSA极大地降低了红细胞清除率至最低水平（0.0024至0.0031 ml/min/单位血细胞比容）。尽管E(1)S（0.027±0.004）和E1（0.036±0.006）的未结合部分较低，但在再循环灌注的大鼠肝脏（流速为0.91±0.1 ml/min/g肝脏）中，灌注液（4% BSA和20%红细胞）中同时注入的示踪剂[(3)H]E(1)S和[(14)C]E1的清除率很高（分别为0.53±0.08和0.85±0.2 ml/min/g肝脏）。尽管在注入示踪剂[(3)H]E(1)S后观察到低水平的[(3)H]E1，但母体和代谢物物种均显示出相似的衰变半衰期，这是经历无效循环的化合物的特征。[(14)C]E(1)S也观察到相同的衰变曲线，但相比之下，注入的[(14)C]E1的半衰期较短。一个串联隔室肝脏模型被用来解释不同的半衰期，该模型纳入了先前观察到的门静脉周围和肝静脉周围肝细胞在雌酮硫酸化和葡萄糖醛酸化活性方面的异质性，以及在肝血窦转运和脱硫方面的同质性。该模型描述了E1在内质网中的高分配以及胞质空间中雌酮硫酸化活性与内质网空间中脱硫和葡萄糖醛酸化活性的分离。
