Lung Retention by Lysosomal Trapping of Inhaled Drugs Can Be Predicted In Vitro With Lung Slices.
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.
Translational PKPD Group, Department of Pharmaceutical Biosciences, Uppsala University, Uppsala 751 24, Sweden; Respiratory, Inflammation and Autoimmunity Innovative Medicines, AstraZeneca R&D Gothenburg, Mölndal 431 83, Sweden. Electronic address: erica.backstrom@astrazeneca.com.
Erica
E
Bäckström
Respiratory, Inflammation and Autoimmunity Innovative Medicines, AstraZeneca R&D Gothenburg, Mölndal 431 83, Sweden; School of Engineering, University of Warwick, Coventry CV4 7AL, United Kingdom.
Elin
E
Boger
Respiratory, Inflammation and Autoimmunity Innovative Medicines, AstraZeneca R&D Gothenburg, Mölndal 431 83, Sweden.
Anders
A
Lundqvist
Translational PKPD Group, Department of Pharmaceutical Biosciences, Uppsala University, Uppsala 751 24, Sweden.
Margareta
M
Hammarlund-Udenaes
Translational PKPD Group, Department of Pharmaceutical Biosciences, Uppsala University, Uppsala 751 24, Sweden; Respiratory, Inflammation and Autoimmunity Innovative Medicines, AstraZeneca R&D Gothenburg, Mölndal 431 83, Sweden.
Markus
M
Fridén
D000280:Administration, Inhalation; D058666:Adrenergic beta-2 Receptor Agonists / Q000008:administration & dosage / Q000378:metabolism*; D000818:Animals; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000378:metabolism*; D005544:Forecasting; D008168:Lung / Q000187:drug effects / Q000378:metabolism*; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009924:Organ Culture Techniques; D051381:Rats; D017208:Rats, Wistar
D058666:Adrenergic beta-2 Receptor Agonists; D001993:Bronchodilator Agents
distribution; pharmacokinetics; pulmonary; pulmonary drug delivery; tissue partition