Pirfenidone Lung Distribution Amplified in Idiopathic Pulmonary Fibrosis: Roles of tight junction disruption and drug transporter dysregulation.

Abstract

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 three 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. In BLM 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 2.1 - 3.4 fold, while overexpression of efflux transporters reduced accumulation by 85 - 89%. These findings suggested that IPF pathogenesis creates a permissive microenvironment for PFD through simultaneous enhancement of paracellular permeability and active cellular uptake. 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.