Jia-Xing Wei, Chao-Yi Li, Wei-Ya Chen, Yi-Jun Cong, Chun-Yu Liu, Fei-Fei Yang, Yong-Hong Liao
Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicines, Ministry of Education, Institute of Medicinal Plant Development (IMPLAD), Chinese Academy of Medical Sciences & Peking Union Medical College, No. 151 Malianwa North Road, Haidian District, Beijing 100193, PR China.
Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicines, Ministry of Education, Institute of Medicinal Plant Development (IMPLAD), Chinese Academy of Medical Sciences & Peking Union Medical College, No. 151 Malianwa North Road, Haidian District, Beijing 100193, PR China.
Biomed Pharmacother. 2023 Apr;160:114335. doi: 10.1016/j.biopha.2023.114335. Epub 2023 Jan 30.
Re-Du-Ning injection (RDN) is a renowned heat-clearing traditional Chinese medicine for the treatment of respiratory diseases owing to its anti-inflammatory effects. However, very little is known about the pulmonary distribution and lung exposure-efficacy relationships. This study aimed to investigate the pulmonary distribution and biopharmaceutics concerning lung penetrability and affinity and the local anti-inflammatory effects after intravenous and pulmonary administration of RDN.
Two iridoids and seven phenolic acid components were selected as the chemical markers in RDN. The in vitro pulmonary distribution and biopharmaceutics were conducted by evaluating the binding and disassociation kinetics of chemical markers in lung tissue explants whereas the in vivo evaluation was performed by determining the time-dependent concentrations of chemical markers in plasma, lung epithelial lining fluid (ELF), lung tissues and immune cells in the ELF after intratracheal and intravenous administrations of RDN. The inhibitory effects on tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) production were used to evaluate the anti-inflammatory effect of RDN on lung tissues in vitro and on mice with LPS-induced lung inflammation.
The chemical markers of RDN exhibited excellent lung penetrability but poor lung affinity in vitro and in vivo. After intravenous administration, the chemical markers appeared to rapidly penetrate through the lung tissue to reach the ELF, leading to markedly higher drug exposure to ELF and immune cells in the ELF than to lung tissues. Compared to intravenous injection, the intratracheal instillation of RDN increased drug exposure to lung tissue and immune cells in the ELF by up to > 80-fold, leading to improved anti-inflammatory potency and prolonged duration of action.
The drug exposure to immune cells in the ELF was correlated with the lung-targeted anti-inflammatory effects of RDN and pulmonary delivery has the potential to replace intravenous injection of RDN for the treatment of respiratory diseases.
热毒宁注射液（RDN）是一种著名的清热类中药，因其抗炎作用而用于治疗呼吸道疾病。然而，关于其肺部分布及肺暴露-药效关系却知之甚少。本研究旨在探讨热毒宁注射液经静脉和肺部给药后的肺部分布、与肺穿透性和亲和力相关的生物药剂学特性以及局部抗炎作用。
选择两种环烯醚萜和七种酚酸成分作为热毒宁注射液的化学标志物。体外肺部分布和生物药剂学研究通过评估化学标志物在肺组织外植体中的结合和解离动力学来进行，而体内评估则通过测定热毒宁注射液经气管内和静脉给药后血浆、肺上皮衬液（ELF）、肺组织及ELF中免疫细胞内化学标志物的时间依赖性浓度来进行。采用对肿瘤坏死因子-α（TNF-α）和白细胞介素-6（IL-6）产生的抑制作用来评估热毒宁注射液在体外对肺组织以及对脂多糖诱导的肺部炎症小鼠的抗炎作用。
热毒宁注射液的化学标志物在体外和体内均表现出良好的肺穿透性，但肺亲和力较差。静脉给药后，化学标志物似乎迅速穿透肺组织到达ELF，导致ELF和ELF中免疫细胞的药物暴露量明显高于肺组织。与静脉注射相比，气管内滴注热毒宁注射液使肺组织和ELF中免疫细胞的药物暴露量增加高达80倍以上，从而提高了抗炎效力并延长了作用持续时间。
ELF中免疫细胞的药物暴露与热毒宁注射液的肺靶向抗炎作用相关，肺部给药有可能替代热毒宁注射液静脉注射用于治疗呼吸道疾病。
