Jagdale Prabhas, Verma Ashwni, Shah Dhaval K
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, The State University of New York at Buffalo, Buffalo, NY 14214, USA.
Pharmaceutics. 2024 Sep 27;16(10):1259. doi: 10.3390/pharmaceutics16101259.
This study aimed to investigate the effect of molecular size on the pulmonary pharmacokinetics (PK) of proteins following systemic and local administration in wild-type mice. A non-cross-reactive antibody trastuzumab, and F(ab')2, Fab, and scFv fragments of this antibody were used for the investigation. Proteins were injected intravenously or via intratracheal instillation, and PK was measured in plasma, lungs, trachea, bronchi, and bronchoalveolar lavage (BAL) using ELISA. Concentrations in BAL were urea normalized. Following systemic administration, the biodistribution coefficient (BC) for lungs, trachea, bronchi, and BAL was 11%, 11%, 15%, and 2% for the antibody; 15%, 7%, 13%, and 8% for F(ab')2; 25%, 17%, 28%, and 46% for Fab; and 14%, 1%, 2%, and 50% for scFv. The antibody exposure in BAL was ~50-fold lower than plasma and ~5-7-fold lower than lung tissues. A tissue-dependent BC vs. molecular size relationship was observed, where distribution in tissues was the highest for Fab (50 kDa), and scFv demonstrated the highest distribution in the BAL. PK data generated following local administration were quite variable; however, local dosing resulted in BAL exposures that were 10-100-fold higher than those achieved after systemic dosing for all proteins. The BAL antibody concentrations were 100-1000-fold higher than plasma concentrations initially, which normalized by day 14. For most proteins, local dosing resulted in higher lung concentrations than trachea and bronchi, opposite to what was observed after systemic dosing. The PK data presented here provide an unprecedented quantitative insight into the effect of molecular size on the pulmonary disposition of proteins following systemic and local administration.
本研究旨在探讨分子大小对野生型小鼠全身和局部给药后蛋白质肺部药代动力学（PK）的影响。使用一种非交叉反应性抗体曲妥珠单抗及其F(ab')2、Fab和单链抗体片段（scFv）进行研究。蛋白质通过静脉注射或气管内滴注给药，并使用酶联免疫吸附测定法（ELISA）在血浆、肺、气管、支气管和支气管肺泡灌洗（BAL）中测量PK。BAL中的浓度以尿素进行标准化。全身给药后，抗体在肺、气管、支气管和BAL中的生物分布系数（BC）分别为11%、11%、15%和2%；F(ab')2分别为15%、7%、13%和8%；Fab分别为25%、17%、28%和46%；scFv分别为14%、1%、2%和50%。BAL中抗体的暴露量比血浆低约50倍，比肺组织低约5 - 7倍。观察到组织依赖性的BC与分子大小的关系，其中Fab（50 kDa）在组织中的分布最高，scFv在BAL中的分布最高。局部给药后产生的PK数据变化很大；然而，局部给药导致所有蛋白质在BAL中的暴露量比全身给药后高10 - 100倍。最初BAL中抗体浓度比血浆浓度高100 - 1000倍，到第14天恢复正常。对于大多数蛋白质，局部给药导致肺中的浓度高于气管和支气管，这与全身给药后观察到的情况相反。此处呈现的PK数据为分子大小对全身和局部给药后蛋白质肺部处置的影响提供了前所未有的定量见解。
