Development of a Novel Lung Slice Methodology for Profiling of Inhaled Compounds

Area of Science:

• Pharmacology
• Drug Delivery
• Inhalation Therapy

Background:

• Optimizing inhaled drug exposure is hindered by challenges in defining unbound drug concentrations at the lung target site.
• Understanding drug distribution within lung tissue is crucial for effective inhaled compound design.

Purpose of the Study:

• To develop and apply a novel rat lung slice methodology for studying drug uptake and its mechanisms in lung tissue.
• To determine the unbound drug volume of distribution in lung (Vu,lung) for various inhaled compounds.

Main Methods:

• Preparation of fresh rat lung slices (500 μm) from drug-naive rats.
• Incubation of lung slices with different drugs.
• Determination of unbound drug volume of distribution in lung (Vu,lung) by measuring total drug concentration in slices versus unbound buffer concentration.
• Co-incubation with monensin to investigate lysosomal trapping mechanisms.

Main Results:

• The unbound drug volume of distribution in lung (Vu,lung) varied significantly across tested compounds, from 2.21 mL/g (salbutamol) to 2970 mL/g (dibasic compound A).
• Monensin inhibited the uptake of basic propranolol by 13%, demonstrating extensive lysosomal trapping.
• High cellular partitioning was observed for MPP+ and dibasic compound A, attributed to carrier-mediated transport and lysosomal trapping.

Conclusions:

• Various factors influence drug uptake in lung tissue.
• The developed rat lung slice method is effective for profiling inhaled compounds.
• This methodology enhances the understanding of drug distribution and exposure within the lung, facilitating improved inhaled drug design.