Covell D G, Barbet J, Holton O D, Black C D, Parker R J, Weinstein J N
Cancer Res. 1986 Aug;46(8):3969-78.
The pharmacokinetics of an immunoglobulin G1 (IgG1) and its F(ab')2 and Fab' fragments following i.v. administration in mice has been studied by constructing a physiologically based, organ-specific model to describe antibody biodistribution, catabolism, and excretion. The antibody selected for study (MOPC-21) has no known binding sites in the body and therefore is useful for defining antibody metabolism by nontumor tissues. Whole IgG remains in the body for 8.3 days, the majority of time in the carcass (53.0% of the total residence time); has a distribution volume exceeding that of plasma plus interstitial fluid; distributes into these volumes rapidly for most enteral organs (equilibration time less than 2.6 min for liver, spleen, kidney, and lung), slower for the gut (less than 20 min), and slowest for the carcass (less than 260 min); produces interstitial:plasma concentration ratios of greater than 0.5 for enteral organs and 0.18 for carcass; has the greatest percentage of its catabolism due to the gut (72.8%), followed by the liver (20.5%), then the spleen (3.6%); has the highest extraction on a single pass by the gut (0.14%) and cycles through the interstitial spaces of the body at least 2.8 times/g of organ weight before being metabolized or excreted. When compared with whole IgG, the Fab' fragment is cleared from the body 35 times faster; has a larger total distribution volume; distributes more rapidly into this volume; produces higher interstitial:plasma concentration ratios; is catabolized principally by the kidney (73.4% of total catabolism), followed by the gut (22.9%), then the spleen (3.1%); is extracted from the circulation to the extent of 3.4% on each pass through the kidney, and less by gut (1.0%) and spleen (0.14%) and cycles through non-kidney interstitial spaces at least 0.4 cycles/g of tissue weight before metabolism or excretion. The F(ab')2 fragment has pharmacokinetic characteristics that fall between those of whole IgG and Fab'. These results provide pharmacokinetic criteria for selecting whole IgG, F(ab')2, or Fab' for various in vivo applications; provide a framework for predicting cumulative tissue exposure to antibody labeled with different isotopes; and provide a reference metabolic state for the analysis of more complex systems that do include antibody binding.
通过构建一个基于生理学的、器官特异性模型来描述抗体的生物分布、分解代谢和排泄，研究了免疫球蛋白G1（IgG1）及其F(ab')2和Fab'片段在小鼠静脉注射后的药代动力学。所选择用于研究的抗体（MOPC - 21）在体内没有已知的结合位点，因此可用于确定非肿瘤组织的抗体代谢情况。完整IgG在体内留存8.3天，大部分时间存在于躯体中（占总留存时间的53.0%）；其分布容积超过血浆加组织间液的容积；对于大多数肠内器官，它能迅速分布到这些容积中（肝脏、脾脏、肾脏和肺的平衡时间少于2.6分钟），肠道分布较慢（少于20分钟），躯体分布最慢（少于260分钟）；肠内器官的组织间液与血浆浓度比大于0.5，躯体的该比值为0.18；其分解代谢最大比例归因于肠道（72.8%），其次是肝脏（20.5%），然后是脾脏（3.6%）；单次通过肠道时的摄取率最高（0.14%），在被代谢或排泄前，以每克器官重量计，在体内组织间液中循环至少2.8次。与完整IgG相比，Fab'片段从体内清除的速度快35倍；总分布容积更大；更快地分布到该容积中；产生更高的组织间液与血浆浓度比；主要由肾脏分解代谢（占总分解代谢的73.4%），其次是肠道（22.9%），然后是脾脏（3.1%）；每次通过肾脏时从循环中的摄取率为3.4%，通过肠道（1.0%）和脾脏（0.14%）的摄取率较低，在代谢或排泄前，以每克组织重量计，在非肾脏组织间液中循环至少0.4次。F(ab')2片段的药代动力学特征介于完整IgG和Fab'之间。这些结果为在各种体内应用中选择完整IgG、F(ab')2或Fab'提供了药代动力学标准；为预测累积组织暴露于不同同位素标记的抗体提供了框架；并为分析确实包含抗体结合的更复杂系统提供了参考代谢状态。
