Altered chain-length and glycosylation modify the pharmacokinetics of human serum albumin

Human serum albumin with modified plasma half-life will be useful for clinical purposes. Therefore, the pharmacokinetics of three of each of the following types of genetic variants, and of their corresponding normal albumin, were examined in mice: N-terminally elongated, C-terminally truncated and glycosylated albumins. Isoforms differing from the normal protein by three or more amino acids, especially two of the truncated forms, had shorter half-lives. The effect of glycosylation depended on the position of attachment: in domain II it increased half-life, whereas in domain I and III it had no significant effect. Liver, kidney and spleen uptake clearances were also modified. The pronounced changes in half-life of the two truncated variants and the glycosylated isoform could be explained, at least partly, by large changes in organ uptakes; in the remaining six cases, different effects were registered. Such information should be useful when designing therapeutical albumin products for, e.g., drug delivery systems. In addition to various types of cell endocytosis, leading to intracellular destruction or recycling of the proteins, the metabolism of the alloalbumins could be affected by plasma enzymes. No correlation was found between mutation-induced changes in the pharmacokinetic parameters and changes in alpha-helical content or changes in heat stability as represented by Delta H-v. (C) 2008 Elsevier B.V. All rights reserved.

具有改变的血浆半衰期的人血清白蛋白将可用于临床目的。因此，在小鼠中检测了以下每种类型的三种遗传变体以及它们相应的正常白蛋白的药代动力学：N末端延长的、C末端截短的和糖基化的白蛋白。与正常蛋白质相差三个或更多氨基酸的异构体，特别是两种截短形式，具有较短的半衰期。糖基化的作用取决于连接位置：在结构域II中它增加半衰期，而在结构域I和III中它没有显著影响。肝脏、肾脏和脾脏的摄取清除率也发生了改变。两种截短变体和糖基化异构体半衰期的显著变化至少可以部分地由器官摄取的大幅变化来解释；在其余六种情况下，记录到了不同的影响。在设计用于例如药物递送系统的治疗性白蛋白产品时，此类信息应该是有用的。除了各种类型的细胞内吞作用（导致蛋白质在细胞内被破坏或再循环）之外，同种白蛋白的代谢可能会受到血浆酶的影响。在药代动力学参数的突变诱导变化与α - 螺旋含量变化或由ΔH - v表示的热稳定性变化之间未发现相关性。（C）2008爱思唯尔有限公司。保留所有权利。