Dissociation from albumin: a potentially rate-limiting step in the clearance of substances by the liver.
Dissociation from albumin: a potentially rate-limiting step in the clearance of substances by the liver.
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与白蛋白的解离：肝脏清除物质的潜在限速步骤。
DOI：
10.1073/pnas.82.5.1563
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发表时间：
1985
影响因子：
11.1
通讯作者：
Weisiger,RA
中科院分区：
文献类型：
--
作者：
Weisiger,RA
某些白蛋白结合药物和代谢产物的肝摄取率与其血浆中的平衡未结合浓度相关性较差，表明结合平衡可能并不总是存在于肝窦内。目前可用的吸收过程模型假设结合平衡，因此，不能用于调查这种可能性。本报告提出了一个更一般的模型，分别处理血浆结合和游离浓度。提供了一种解决方案，该解决方案规定了肝摄取速率作为转运物质和结合蛋白的总血浆浓度以及流入、流出、消除、缔合、解离和流动的速率常数的函数。对该溶液的分析表明，肝脏摄取可能受到血浆流速、与结合蛋白的解离、流入肝脏、细胞消除或这些过程的任何组合的限制。结合蛋白的亲和力和浓度强烈影响这些步骤中的哪一个在任何给定情况下是限速的，并且仅当结合蛋白浓度大于指定值（摄取和结合速率常数的比率）时，肝窦内才存在结合平衡。精确的条件下，每个步骤是限速和动力学行为时，两个或两个以上的步骤相互限制摄取预期提供。这些结果与先前报道的某些白蛋白结合配体（如胆红素）的摄取数据相一致，并且它们提供了将这些动力学归因于白蛋白受体存在的替代方法。
The hepatic uptake rate for certain albumin-bound drugs and metabolites correlates poorly with their equilibrium unbound concentration in the plasma, suggesting that binding equilibrium may not always exist within the hepatic sinusoids. Currently available models for the uptake process assume binding equilibrium and, thus, cannot be used to investigate this possibility. This report presents a more general model that treats plasma-bound and free concentrations separately. A solution is provided that specifies the hepatic uptake rate as a function of the total plasma concentrations of the transported substance and of binding protein and the rate constants for influx, efflux, elimination, association, dissociation, and flow. Analysis of this solution indicates that hepatic uptake may be limited by the rate of plasma flow, dissociation from the binding protein, influx into the liver, cellular elimination, or any combination of these processes. The affinity and concentration of the binding protein strongly influence which of these steps are rate-limiting in any given case, and binding equilibrium exists within the hepatic sinusoids only for binding protein concentrations greater than a specified value (the ratio of the uptake and association rate constants). The precise conditions under which each step is rate-limiting and the kinetic behavior expected when two or more steps mutually limit uptake are provided. The results are compatible with previously reported data for the uptake of certain albumin-bound ligands such as bilirubin, and they offer an alternative to attributing these kinetics to the presence of an albumin receptor.