Lung Retention by Lysosomal Trapping of Inhaled Drugs Can Be Predicted In Vitro With Lung Slices

• Published in: Journal of pharmaceutical sciences 2016-11, Vol.105 (11), p.3432-3439
• Main Authors: Bäckström, Erica, Boger, Elin, Lundqvist, Anders, Hammarlund-Udenaes, Margareta, Fridén, Markus
• Format: Article
• Language: English
• Subjects: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists - administration & dosage; Adrenergic beta-2 Receptor Agonists - metabolism; Animals; Bronchodilator Agents - administration & dosage; Bronchodilator Agents - metabolism; distribution; Forecasting; Lung - drug effects; Lung - metabolism; Lysosomes - drug effects; Lysosomes - metabolism; Male; Organ Culture Techniques; pharmacokinetics; pulmonary; pulmonary drug delivery; Rats; Rats, Wistar; tissue partition
• ISSN: 0022-3549; 1520-6017; 1520-6017
• DOI: 10.1016/j.xphs.2016.08.014

Modulating and optimizing the local pharmacokinetics of inhaled drugs by chemical design or formulation is challenged by the lack of predictive in vitro systems and in vivo techniques providing a detailed description of drug location in the lung. The present study investigated whether a new experimental setup of freshly prepared agarose-filled lung slices can be used to estimate lung retention in vitro, by comparing with in vivo lung retention after intratracheal instillation. Slices preloaded with inhaled β-adrenergic compounds (salbutamol, formoterol, salmeterol, indacaterol or AZD3199) were incubated in a large volume of buffer (w/wo monensin to assess the role of lysosomal trapping), and the amount remaining in slices at different time points was determined with liquid chromatography-tandem mass spectrometry. The in vitro lung retention closely matched the in vivo lung retention (half-lives within 3-fold for 4/5 compounds), and monensin shortened the half-lives for all compounds. The results suggest that freshly prepared rat lungs slices can be used to predict lung retention and that slow kinetics of lysosomal trapping is a key mechanism by which retention in the lung and the effect duration of inhaled β-adrenergic bronchodilators are prolonged.