Hong G, Bazin-Redureau M I, Scherrmann J M
Inserm U26 and Department of Pharmacokinetics, University of Paris V, Hôpital Fernand Widal, Paris, France.
J Pharm Sci. 1999 Jan;88(1):147-53. doi: 10.1021/js970335n.
Pharmacokinetics of cationized goat colchicine-specific polyclonal immunoglobulin G (IgG) and antigen binding fragment (Fab) (cIgG and cFab, respectively) were studied in male adult Sprague-Dawley rats and compared with those of the native proteins (nIgG and nFab). All proteins were radioiodinated by the Iodogen method, and kinetics were investigated following trichloroacetic acid (TCA) precipitation or immunoprecipitation. Deiodination and catabolism were more pronounced with the cationized than the native proteins, especially for cFab. Both cIgG and cFab in plasma decreased more rapidly than nIgG and nFab. The elimination half-lives were 52.9 and 81.8 h for cIgG and nIgG, respectively. In addition, there was a 74-fold increase in the volume of distribution and a 114-fold increase in the systemic clearance of cIgG compared with nIgG. For cFab, the volume of distribution and systemic clearance were increased 6.4- and 3.5-fold, respectively. Organ uptake of cIgG and cFab was markedly increased compared with that of nIgG and nFab, especially in kidney, liver, spleen, and lung. Renal clearance of cIgG and cFab was also increased 30- and 10-fold compared with that of nIgG and nFab, respectively. The present data suggest that cationization of colchicine-specific IgG and Fab fragments increased the organ distribution and greatly altered their pharmacokinetics. Nevertheless, the smaller molecular size of Fab versus IgG did not enhance the distribution and clearance of cFab. These data pave the way for evaluating the biological efficacy of these more tissue-organ-interactive antibodies.
在成年雄性Sprague-Dawley大鼠中研究了阳离子化的抗秋水仙碱特异性山羊多克隆免疫球蛋白G（IgG）和抗原结合片段（Fab）（分别为cIgG和cFab）的药代动力学，并与天然蛋白（nIgG和nFab）进行了比较。所有蛋白质均采用碘酰法进行放射性碘化，并在三氯乙酸（TCA）沉淀或免疫沉淀后研究其动力学。与天然蛋白相比，阳离子化蛋白的脱碘和分解代谢更为明显，尤其是cFab。血浆中的cIgG和cFab均比nIgG和nFab下降得更快。cIgG和nIgG的消除半衰期分别为52.9小时和81.8小时。此外，与nIgG相比，cIgG的分布容积增加了74倍，全身清除率增加了114倍。对于cFab，分布容积和全身清除率分别增加了6.4倍和3.5倍。与nIgG和nFab相比，cIgG和cFab在器官中的摄取明显增加，尤其是在肾脏、肝脏、脾脏和肺中。cIgG和cFab的肾清除率也分别比nIgG和nFab增加了30倍和10倍。目前的数据表明，秋水仙碱特异性IgG和Fab片段的阳离子化增加了器官分布并极大地改变了它们的药代动力学。然而，Fab相对IgG较小的分子大小并未增强cFab的分布和清除。这些数据为评估这些与组织器官相互作用更强的抗体的生物学功效铺平了道路。
