Pirfenidone Lung Distribution is Amplified in Idiopathic Pulmonary Fibrosis: Critical roles of tight junction disruption and drug transporter dysregulation

Pirfenidone Lung Distribution is Amplified in Idiopathic Pulmonary Fibrosis: Critical roles of tight junction disruption and drug transporter dysregulation | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 9 July 2025 V1 Latest version Share on Pirfenidone Lung Distribution is Amplified in Idiopathic Pulmonary Fibrosis: Critical roles of tight junction disruption and drug transporter dysregulation Authors : Xiaoting Gu , Chaoyue Zheng , Bo Li , Keran Li , Xiaohe Li 0000-0003-4315-5953 , Shaoyan Gao , Jia Zhang , … Show All … , Xiaoting Wang , Conglu Zhao , Xiang Xu , Cheng Yang , Xueren Li , Shouchun Peng , Xiaoyu Ai [email protected] , Na Yu , and Honggang Zhou Show Fewer Authors Info & Affiliations https://doi.org/10.22541/au.175205908.83832169/v1 207 views 133 downloads Contents Abstract Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Abstract Background and Purpose: Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disorder characterized by alveolar destruction and excessive collagen deposition, with pirfenidone (PFD) being one of only two approved therapies worldwide. Current understanding of how IPF pathology affects PFD lung tissue distribution remains limited. Here, we identified significant alterations in both tight junction proteins and drug transporters in bleomycin-induced fibrotic lungs, revealing a dual mechanism for preferential PFD distribution. Experimental Approach: In IPF rats, we observed a 2.4-fold increase in pulmonary PFD accumulation despite a 27% reduction in plasma AUC. This finding was accompanied by marked downregulation of tight junction proteins, including ZO-1, occludin, claudin-3 and claudin-5, which correlated with impaired alveolar barrier integrity. Additionally, we identified coordinated dysregulation of drug transporters, with upregulation of uptake transporters (OCT1, OCT3, OCTN2 and SLC3A2) and downregulation of efflux transporters (MRP1, MRP4 and MRP5). Functional studies demonstrated that overexpression of uptake transporters enhanced intracellular PFD levels by 3.1 – 4.4 fold, while overexpression of efflux transporters reduced accumulation by 85 -89 %. Key Results: These findings suggested that IPF pathogenesis creates a permissive microenvironment for PFD through simultaneous enhancement of paracellular permeability and active cellular uptake. Conclusion and Implications: This study provided a new perspective for an in-depth understanding of the mechanism of action of PFD in IPF therapy and lay a theoretical foundation for optimising the clinical drug strategy. Supplementary Material File (manuscript.docx) Download 10.17 MB Information & Authors Information Version history V1 Version 1 09 July 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Authors Affiliations Xiaoting Gu Nankai University State Key Laboratory of Medicinal Chemical Biology View all articles by this author Chaoyue Zheng Nankai University State Key Laboratory of Medicinal Chemical Biology View all articles by this author Bo Li Jinzhou Medical University View all articles by this author Keran Li Nankai University State Key Laboratory of Medicinal Chemical Biology View all articles by this author Xiaohe Li 0000-0003-4315-5953 Nankai University State Key Laboratory of Medicinal Chemical Biology View all articles by this author Shaoyan Gao Nankai University State Key Laboratory of Medicinal Chemical Biology View all articles by this author Jia Zhang Nankai University State Key Laboratory of Medicinal Chemical Biology View all articles by this author Xiaoting Wang Nankai University State Key Laboratory of Medicinal Chemical Biology View all articles by this author Conglu Zhao Nankai University State Key Laboratory of Medicinal Chemical Biology View all articles by this author Xiang Xu Nankai University State Key Laboratory of Medicinal Chemical Biology View all articles by this author Cheng Yang Nankai University State Key Laboratory of Medicinal Chemical Biology View all articles by this author Xueren Li Tianjin University Tianjin Hospital View all articles by this author Shouchun Peng Tianjin University Tianjin Hospital View all articles by this author Xiaoyu Ai [email protected] Nankai University State Key Laboratory of Medicinal Chemical Biology View all articles by this author Na Yu The First Hospital of China Medical University Institute of Respiratory Disease View all articles by this author Honggang Zhou Nankai University State Key Laboratory of Medicinal Chemical Biology View all articles by this author Metrics & Citations Metrics Article Usage 207 views 133 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Xiaoting Gu, Chaoyue Zheng, Bo Li, et al. Pirfenidone Lung Distribution is Amplified in Idiopathic Pulmonary Fibrosis: Critical roles of tight junction disruption and drug transporter dysregulation. Authorea . 09 July 2025. DOI: https://doi.org/10.22541/au.175205908.83832169/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu . 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