Three-Compartment Pharmacokinetics of Inhaled and Injected Sinapine Thiocyanate Manifest Prolonged Retention and Its Therapeutics in Acute Lung Injury
<b>Background</b>: Acute lung injury (ALI) is driven by inflammatory cascades and reactive oxygen species (ROS) generation, with the progression to severe cases markedly increasing mortality. Sinapine thiocyanate (ST), a bioactive natural compound isolated from Sinapis Semen Albae (SSA),...
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| author | Zixin Li Caifen Wang Huipeng Xu Qian Wu Ningning Peng Lu Zhang Hui Wang Li Wu Zegeng Li Qinjun Yang Jiwen Zhang |
| author_facet | Zixin Li Caifen Wang Huipeng Xu Qian Wu Ningning Peng Lu Zhang Hui Wang Li Wu Zegeng Li Qinjun Yang Jiwen Zhang |
| author_sort | Zixin Li |
| collection | DOAJ |
| description | <b>Background</b>: Acute lung injury (ALI) is driven by inflammatory cascades and reactive oxygen species (ROS) generation, with the progression to severe cases markedly increasing mortality. Sinapine thiocyanate (ST), a bioactive natural compound isolated from Sinapis Semen Albae (SSA), demonstrates both anti-inflammatory and antioxidant pharmacological activities. However, no monotherapeutic formulation of ST has been developed to date. A dry powder inhaler (DPI) enables targeted pulmonary drug delivery with excellent stability profiles and high inhalation efficiency. <b>Methods</b>: ST was purified and prepared as inhalable dry powder particles via an antisolvent crystallization technique. The therapeutic mechanisms of ST against ALI were elucidated by network pharmacology and pharmacokinetic analyses, with the therapeutic efficacy of the ST DPI in ALI mitigation being validated using LPS-induced rat models. <b>Results</b>: The ST DPI showed ideal aerodynamic characteristics. Notably, ST exhibited a three-compartment (triexponential) pharmacokinetic profile following both intravenous tail vein injection and inhalation administration. Furthermore, the inhaled formulation displayed a prolonged systemic residence time, which confers therapeutic advantages for pulmonary disease management. Furthermore, the inhalation administration of ST demonstrated a 2.7-fold increase in AUC compared with oral gavage, with a corresponding enhancement in systemic exposure. The ST DPI formulation demonstrated significant therapeutic efficacy against ALI in rats by downregulating inflammatory cytokines and modulating oxidative stress levels, mechanistically achieved through the MAPK-mediated regulation of cellular apoptosis via a positive feedback loop. <b>Conclusions</b>: The unique triexponential plasma level profiles of an ST DPI provide a promising pharmacokinetics-based therapeutic strategy for ALI, leveraging its marked efficacy in attenuating inflammation, oxidative stress, and pulmonary injury. |
| format | Article |
| id | doaj-art-0ebd8b84ab1244d69d328443ab4eba07 |
| institution | Kabale University |
| issn | 1999-4923 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj-art-0ebd8b84ab1244d69d328443ab4eba072025-08-20T03:32:15ZengMDPI AGPharmaceutics1999-49232025-07-0117790910.3390/pharmaceutics17070909Three-Compartment Pharmacokinetics of Inhaled and Injected Sinapine Thiocyanate Manifest Prolonged Retention and Its Therapeutics in Acute Lung InjuryZixin Li0Caifen Wang1Huipeng Xu2Qian Wu3Ningning Peng4Lu Zhang5Hui Wang6Li Wu7Zegeng Li8Qinjun Yang9Jiwen Zhang10College of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, ChinaCenter for Drug Delivery Systems, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201210, ChinaCenter for Drug Delivery Systems, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201210, ChinaCenter for Drug Delivery Systems, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201210, ChinaCenter for Drug Delivery Systems, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201210, ChinaCollege of Chinese Medicine, Anhui University of Chinese Medicine, Hefei 230038, ChinaCollege of Chinese Medicine, Anhui University of Chinese Medicine, Hefei 230038, ChinaCenter for Drug Delivery Systems, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201210, ChinaDepartment of Respiratory, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei 230031, ChinaCollege of Chinese Medicine, Anhui University of Chinese Medicine, Hefei 230038, ChinaCollege of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, China<b>Background</b>: Acute lung injury (ALI) is driven by inflammatory cascades and reactive oxygen species (ROS) generation, with the progression to severe cases markedly increasing mortality. Sinapine thiocyanate (ST), a bioactive natural compound isolated from Sinapis Semen Albae (SSA), demonstrates both anti-inflammatory and antioxidant pharmacological activities. However, no monotherapeutic formulation of ST has been developed to date. A dry powder inhaler (DPI) enables targeted pulmonary drug delivery with excellent stability profiles and high inhalation efficiency. <b>Methods</b>: ST was purified and prepared as inhalable dry powder particles via an antisolvent crystallization technique. The therapeutic mechanisms of ST against ALI were elucidated by network pharmacology and pharmacokinetic analyses, with the therapeutic efficacy of the ST DPI in ALI mitigation being validated using LPS-induced rat models. <b>Results</b>: The ST DPI showed ideal aerodynamic characteristics. Notably, ST exhibited a three-compartment (triexponential) pharmacokinetic profile following both intravenous tail vein injection and inhalation administration. Furthermore, the inhaled formulation displayed a prolonged systemic residence time, which confers therapeutic advantages for pulmonary disease management. Furthermore, the inhalation administration of ST demonstrated a 2.7-fold increase in AUC compared with oral gavage, with a corresponding enhancement in systemic exposure. The ST DPI formulation demonstrated significant therapeutic efficacy against ALI in rats by downregulating inflammatory cytokines and modulating oxidative stress levels, mechanistically achieved through the MAPK-mediated regulation of cellular apoptosis via a positive feedback loop. <b>Conclusions</b>: The unique triexponential plasma level profiles of an ST DPI provide a promising pharmacokinetics-based therapeutic strategy for ALI, leveraging its marked efficacy in attenuating inflammation, oxidative stress, and pulmonary injury.https://www.mdpi.com/1999-4923/17/7/909sinapine thiocyanatedry powder inhalerpharmacokineticacute lung injuryMAPK signaling pathway |
| spellingShingle | Zixin Li Caifen Wang Huipeng Xu Qian Wu Ningning Peng Lu Zhang Hui Wang Li Wu Zegeng Li Qinjun Yang Jiwen Zhang Three-Compartment Pharmacokinetics of Inhaled and Injected Sinapine Thiocyanate Manifest Prolonged Retention and Its Therapeutics in Acute Lung Injury Pharmaceutics sinapine thiocyanate dry powder inhaler pharmacokinetic acute lung injury MAPK signaling pathway |
| title | Three-Compartment Pharmacokinetics of Inhaled and Injected Sinapine Thiocyanate Manifest Prolonged Retention and Its Therapeutics in Acute Lung Injury |
| title_full | Three-Compartment Pharmacokinetics of Inhaled and Injected Sinapine Thiocyanate Manifest Prolonged Retention and Its Therapeutics in Acute Lung Injury |
| title_fullStr | Three-Compartment Pharmacokinetics of Inhaled and Injected Sinapine Thiocyanate Manifest Prolonged Retention and Its Therapeutics in Acute Lung Injury |
| title_full_unstemmed | Three-Compartment Pharmacokinetics of Inhaled and Injected Sinapine Thiocyanate Manifest Prolonged Retention and Its Therapeutics in Acute Lung Injury |
| title_short | Three-Compartment Pharmacokinetics of Inhaled and Injected Sinapine Thiocyanate Manifest Prolonged Retention and Its Therapeutics in Acute Lung Injury |
| title_sort | three compartment pharmacokinetics of inhaled and injected sinapine thiocyanate manifest prolonged retention and its therapeutics in acute lung injury |
| topic | sinapine thiocyanate dry powder inhaler pharmacokinetic acute lung injury MAPK signaling pathway |
| url | https://www.mdpi.com/1999-4923/17/7/909 |
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