Chen Wei-Ya1, Yang Fei-Fei1, Li Cui2, Li Wen-Hui3, Hu Jie4, Liao Yong-Hong5. 1. Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, 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. 2. Increasepharm (Hengqin) Institute Coporation Limited, No. 2522 Huan Dao North Road, Hengqin New Area, Zhuhai, 519000, PR China. 3. Beijing Increasepharm Coporation Limited, Changping District, Beijing, 102200, PR China. 4. Beijing Increasepharm Coporation Limited, Changping District, Beijing, 102200, PR China. Electronic address: jiehu@ykrskj.com. 5. Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, 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. Electronic address: yhliao@implad.ac.cn.
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE: The off-label nebulization of Shuang-Huang-Lian (SHL) injection is often utilized to treat respiratory tract infections in China. However, the pulmonary biopharmaceutics of SHL was generally unknown, limiting the rational selection of therapeutic dose and dose frequency. AIM OF THE STUDY: To characterize the size distribution of nebulized aerosols and to compare the pharmacokinetics and the lung distribution of three chemical makers of SHL, chlorogenic acid (CHA), forsythiaside A (FTA) and baicalin (BC), after intratracheal and intravenous administration of SHL to rats. MATERIALS AND METHODS: The droplet size distribution profiles over nebulization process were dynamically monitored using a laser diffraction method whereas the levels of CHA, FTA and BC in plasma, lung tissues and bronchoalveolar lavage fluids (BALF) were determined by a validated LC-MS/MS assay. The pulmonary anti-inflammatory efficacy was evaluated using a lipopolysaccharide (LPS) induced lung inflammation model as indicated by the level of tumor necrosis factor-α (TNF-α) in BALF. RESULTS: The nebulization of SHL showed good inhalability and allowed the aerosols to reach the upper or lower respiratory tract dependent on the performance of selected nebulizers. Following intratracheal administration of SHL at different doses, CHA, FTA and BC were absorbed into the bloodstream with the mean absorption time being 67.5, 63.5 and 114 min, respectively, rendering mean absolute bioavailabilities between 42.4% and 61.4% roughly independent of delivered dose. Relative to the intravenous injection, the intrapulmonary delivery increased the lung-to-plasma concentration ratios of CHA, FTA and BC by more than 100 folds and markedly improved the lung availability by 563-676 folds, leading to enhanced and prolonged lung retention. The production of TNF-α in BALF was decreased by ~50% at an intratracheal dose of 125 μL/kg SHL to LPS-treated mice. CONCLUSION: The nebulization delivery of SHL is a promising alternative to the intravenous injection for the treatment of respiratory tract infections.
ETHNOPHARMACOLOGICAL RELEVANCE: The off-label nebulization of Shuang-Huang-Lian (SHL) injection is often utilized to treat respiratory tract infections in China. However, the pulmonary biopharmaceutics of SHL was generally unknown, limiting the rational selection of therapeutic dose and dose frequency. AIM OF THE STUDY: To characterize the size distribution of nebulized aerosols and to compare the pharmacokinetics and the lung distribution of three chemical makers of SHL, chlorogenic acid (CHA), forsythiaside A (FTA) and baicalin (BC), after intratracheal and intravenous administration of SHL to rats. MATERIALS AND METHODS: The droplet size distribution profiles over nebulization process were dynamically monitored using a laser diffraction method whereas the levels of CHA, FTA and BC in plasma, lung tissues and bronchoalveolar lavage fluids (BALF) were determined by a validated LC-MS/MS assay. The pulmonary anti-inflammatory efficacy was evaluated using a lipopolysaccharide (LPS) induced lung inflammation model as indicated by the level of tumor necrosis factor-α (TNF-α) in BALF. RESULTS: The nebulization of SHL showed good inhalability and allowed the aerosols to reach the upper or lower respiratory tract dependent on the performance of selected nebulizers. Following intratracheal administration of SHL at different doses, CHA, FTA and BC were absorbed into the bloodstream with the mean absorption time being 67.5, 63.5 and 114 min, respectively, rendering mean absolute bioavailabilities between 42.4% and 61.4% roughly independent of delivered dose. Relative to the intravenous injection, the intrapulmonary delivery increased the lung-to-plasma concentration ratios of CHA, FTA and BC by more than 100 folds and markedly improved the lung availability by 563-676 folds, leading to enhanced and prolonged lung retention. The production of TNF-α in BALF was decreased by ~50% at an intratracheal dose of 125 μL/kg SHL to LPS-treated mice. CONCLUSION: The nebulization delivery of SHL is a promising alternative to the intravenous injection for the treatment of respiratory tract infections.