Abstract
Increasing affinity to lung tissue is an important strategy to achieve pulmonary retention and to prolong the duration of effect in the lung. As the lung is a very heterogeneous organ, differences in structure and blood flow may influence local pulmonary disposition. Here, a novel lung preparation technique was employed to investigate regional lung distribution of four drugs (salmeterol, fluticasone propionate, linezolid, and indomethacin) after intravenous administration in rats. A semi-mechanistic model was used to describe the observed drug concentrations in the trachea, bronchi, and the alveolar parenchyma based on tissue specific affinities (Kp) and blood flows. The model-based analysis was able to explain the pulmonary pharmacokinetics (PK) of the two neutral and one basic model drugs, suggesting up to six-fold differences in Kp between trachea and alveolar parenchyma for salmeterol. Applying the same principles, it was not possible to predict the pulmonary PK of indomethacin, indicating that acidic drugs might show different pulmonary PK characteristics. The separate estimates for local Kp, tracheal and bronchial blood flow were reported for the first time. This work highlights the importance of lung physiology- and drug-specific parameters for regional pulmonary tissue retention. Its understanding is key to optimize inhaled drugs for lung diseases.
Highlights
Pulmonary drug delivery is the preferred administration route for treatment of respiratory disorders like asthma or chronic obstructive pulmonary disease
The alveolar region is stronger perfused compared to the conducting airways, as the alveolar region is perfused by the pulmonary circulation, whereas the conducting airways are perfused by the systemic circulation
This study presents a method towards understanding localized pulmonary retention based on tissue affinity and pulmonary blood flow
Summary
Pulmonary drug delivery is the preferred administration route for treatment of respiratory disorders like asthma or chronic obstructive pulmonary disease. The alveolar region is stronger perfused compared to the conducting airways, as the alveolar region is perfused by the pulmonary circulation, whereas the conducting airways are perfused by the systemic circulation All these physiological differences potentially influence drug pharmacokinetics (PK), raising the question if total lung concentrations are a valid surrogate for target-site concentrations. Β2-receptors are expressed in all lung regions [5], yet the relaxation of smooth muscle cells by inhaled sympathomimetics is driven by receptor activation in the conducting airways. This means that only the drug concentrations in the conducting airways elicit the desired effect. It is key to understand the PK in the local tissues and for the complete lung
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