Influence of inflammation on drug transporter expression in human airway epithelia: Implications for inhaled drug pharmacokinetics.

The efficacy of inhaled drugs is significantly influenced by airway epithelial transporters that mediate their transport and distribution. Because inhaled drugs are used across diverse populations with inflammatory airway diseases, understanding factors that modulate transporter expression is crucial. Therefore, we investigated how inflammatory states, demographic factors, and airway anatomic location impact drug transporter abundance. Using quantitative targeted absolute proteomics, we measured transporter abundance in primary human bronchial epithelia (HBE) from 42 demographically diverse donors. To model distinct inflammatory environments, HBE were exposed to interleukin (IL)-1β (T-helper type [TH]1/neutrophilic inflammation) or IL-13 (TH2/eosinophilic inflammation) for 4 days, alongside baseline controls. We also measured transporter protein concentrations in small airway HBE from 5 donors to assess regional influence. In the primary set of HBE, multidrug resistance protein (MRP)1 (3.96 ± 1.64 pmol/mg protein) and peptide transporter 2 (3.12 ± 0.95 pmol/mg protein) were the most abundant transporters, and their concentrations were responsive to inflammatory signals. Specifically, IL-1β significantly reduced MRP1 (0.80-fold) and peptide transporter 2 (0.65-fold), whereas IL-13 modestly increased MRP1 (1.1-fold) but reduced peptide transporter 2 (0.73-fold) and novel organic cation transporter (OCTN)1 (0.44-fold). Several transporters present at lower abundance, including MRP4, MRP5, MRP6, and OCTN1, were also impacted by inflammation. Demographic factors also played a role, with MRP4 higher in females, and age positively correlated with MRP6 but negatively with OCTN1. Analysis of small airway-derived HBE did not show a significant impact of anatomic location on transporter abundance. Our findings demonstrate that airway inflammation and donor demographics significantly impact the protein expression of key drug transporters, highlighting dynamic factors crucial for optimizing inhaled drug delivery and efficacy. SIGNIFICANCE STATEMENT: Human airway epithelia express multiple transporters, with multidrug resistance protein 1 and peptide transporter 2 present at the highest levels. Transporter abundance is influenced by inflammation, age, and biological sex, but not by airway anatomic location. This information can guide the modeling of inhaled drug pharmacokinetics.