Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14260, USA.
Int J Pharm. 2012 Dec 15;439(1-2):8-16. doi: 10.1016/j.ijpharm.2012.09.042. Epub 2012 Sep 24.
The current work examines the role of Fcγ-receptors on the elimination and tissue distribution of 8C2, a model murine IgG1 monoclonal antibody. The plasma pharmacokinetics of (125)Iodine-labeled 8C2 were investigated in C57BL/6 control mice, FcγRI/RIII knockout mice, and FcγRIIb knockout mice, following intravenous doses of 0.04, 0.1 and 0.4 mg/kg. Plasma samples were collected and radioactivity was counted. Concentration data were analyzed with a population pharmacokinetic model. Additionally, the tissue disposition of 8C2 was investigated using whole body autoradioluminography (WBAL) and via counting excised tissues. Areas under the plasma concentration vs. time curves AUC(0-10 days) ±SD (nM×days) were: 12.3±0.3, 12.5±1.3 and 15.1±1.2 at 0.04 mg/kg; 39.3±2.0, 28.9±2.7 and 42.0±9.4 at 0.1 mg/kg; and 225±19, 158±19 and 204±26 at 0.4 mg/kg in C57BL/6, FcγRI/RIII(-/-) and FcγRIIb(-/-) mice. Strain was not a statistically significant predictor for any of the parameters of the population model. 8C2 plasma clearance, distribution clearance, and central compartment volume were 0.00543 L/days/kg, 0.0598 L/days/kg, and 0.057 L/kg. No substantial differences in 8C2 tissue uptake were identified by analysis of excised tissues or by WBAL. In conclusion, FcγR knockout is associated with only minor effects on the plasma and tissue disposition of 8C2, a model murine IgG1 mAb.
目前的工作研究了 Fcγ-受体在 8C2（一种模型鼠 IgG1 单克隆抗体）的清除和组织分布中的作用。在静脉注射 0.04、0.1 和 0.4mg/kg 的 125I 标记的 8C2 后，在 C57BL/6 对照小鼠、FcγRI/RIII 基因敲除小鼠和 FcγRIIb 基因敲除小鼠中研究了（125）碘标记的 8C2 的血浆药代动力学。收集血浆样本并计数放射性。使用群体药代动力学模型分析浓度数据。此外，通过全身放射自显影（WBAL）和计数切除组织研究了 8C2 的组织分布。血浆浓度-时间曲线下面积 AUC（0-10 天）±SD（nM×天）为：0.04mg/kg 时为 12.3±0.3、12.5±1.3 和 15.1±1.2；0.1mg/kg 时为 39.3±2.0、28.9±2.7 和 42.0±9.4；0.4mg/kg 时为 225±19、158±19 和 204±26，在 C57BL/6、FcγRI/RIII（-/-）和 FcγRIIb（-/-）小鼠中。品系不是群体模型中任何参数的统计学上显著预测因子。8C2 血浆清除率、分布清除率和中央室容积分别为 0.00543 L/days/kg、0.0598 L/days/kg 和 0.057 L/kg。通过对切除组织或 WBAL 的分析，未发现 8C2 组织摄取有实质性差异。总之，FcγR 敲除仅对 8C2 的血浆和组织分布产生微小影响，8C2 是一种模型鼠 IgG1 mAb。
