Abstract
Idiopathic Pulmonary Fibrosis (IPF) represents a life-threatening disease with poor prognosis and limited treatment options. Pirfenidone is the only drug approved in for the treatment of IPF, although its precise mechanism of action remains unclear. The presence and distribution of Pirfenidone within different compartments, and whether its administration routs has any metabolic effect during treatment is unknown.
10 week old mice were treated with pirfenidone or control orally for 10, 30, 45, 60, 90, and 180 min (n=4). Fibrosis was induced by bleomycin, at day 7 mice were treated orally with 500mg/kg of Pirfenidone daily, and harvested 7 days later. Tissue was snap frozen and used for in-situ identification of targets via MALDI-imaging.
In-situ distribution of pirfenidone and its relevant metabolites: 5-hydroxymethyl pirfenidone and 5-carboxylic acid pirfenidone was successfully achieved and analyzed qualitatively and quantitatively. Exhaustive kinetics allowed us detail quantification and organ specific drug and metabolites distribution from the initial peaks (30min) to complete excretion. Different administration routs (PO vs IT) showed distinct metabolite dynamics and distribution to the liver. Endogenous metabolic pathways (e.g. Purine and Pyrimidine biosynthesis, Glycolysis) alterations were detected in fibrotic vs healthy lung (e.g. Glutathione).
Our results are helping us to gain more insight in drug distribution and destination in fibrotic tissue, further experiments of in-situ correlation with ECM niches and cell-type specific compartments are ongoing. This will help us improving the current available therapy, and develop high-tech methods for up-coming drugs.
- © 2014 ERS