title: Development of a Novel Lung Slice Methodology for Profiling of Inhaled Compounds.
abstract: The challenge of defining the concentration of unbound drug at the lung target site after inhalation limits the possibility to optimize target exposure by compound design. In this study, a novel rat lung slice methodology has been developed and applied to study drug uptake in lung tissue, and the mechanisms by which this occurs. Freshly prepared lung slices (500 μm) from drug-naive rats were incubated with drugs followed by determination of the unbound drug volume of distribution in lung (Vu,lung), as the total concentration of drug in slices divided by the buffer (unbound) concentration. Vu,lung determined for a set of inhaled drug compounds ranged from 2.21 mL/g for salbutamol to 2970 mL/g for dibasic compound A. Co-incubation with monensin, a modulator of lysosomal pH, resulted in inhibition of tissue uptake of basic propranolol to 13%, indicating extensive lysosomal trapping. Partitioning into cells was particularly high for the cation MPP+ and the dibasic compound A, likely because of the carrier-mediated transport and lysosomal trapping. The results show that different factors are important for tissue uptake and the presented method can be used for profiling of inhaled compounds, leading to a greater understanding of distribution and exposure of drug in the lung.
authors.affiliation: Translational PKPD, Department of Pharmaceutical Biosciences, Uppsala University, Uppsala 751 24, Sweden; Respiratory, Inflammation and Autoimmunity Innovative Medicines, AstraZeneca R&D, Mölndal 431 83, Sweden. Electronic address: erica.backstrom@astrazeneca.se.
authors.forename: Erica
authors.initials: E
authors.lastname: Bäckström
authors.affiliation: Respiratory, Inflammation and Autoimmunity Innovative Medicines, AstraZeneca R&D, Mölndal 431 83, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Lundqvist
authors.affiliation: Respiratory, Inflammation and Autoimmunity Innovative Medicines, AstraZeneca R&D, Mölndal 431 83, Sweden; School of Engineering, University of Warwick CV4 7AL, Coventry, United Kingdom.
authors.forename: Elin
authors.initials: E
authors.lastname: Boger
authors.affiliation: Respiratory, Inflammation and Autoimmunity Innovative Medicines, AstraZeneca R&D, Mölndal 431 83, Sweden.
authors.forename: Petter
authors.initials: P
authors.lastname: Svanberg
authors.affiliation: Respiratory, Inflammation and Autoimmunity Innovative Medicines, AstraZeneca R&D, Mölndal 431 83, Sweden.
authors.forename: Pär
authors.initials: P
authors.lastname: Ewing
authors.affiliation: Translational PKPD, Department of Pharmaceutical Biosciences, Uppsala University, Uppsala 751 24, Sweden.
authors.forename: Margareta
authors.initials: M
authors.lastname: Hammarlund-Udenaes
authors.affiliation: Translational PKPD, Department of Pharmaceutical Biosciences, Uppsala University, Uppsala 751 24, Sweden; Respiratory, Inflammation and Autoimmunity Innovative Medicines, AstraZeneca R&D, Mölndal 431 83, Sweden.
authors.forename: Markus
authors.initials: M
authors.lastname: Fridén
mesh_terms: D000280:Administration, Inhalation; D000420:Albuterol / Q000494:pharmacology; D000818:Animals; D001993:Bronchodilator Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008168:Lung / Q000187:drug effects* / Q000502:physiology; D008297:Male; D009924:Organ Culture Techniques; D011433:Propranolol / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014022:Tissue Survival / Q000187:drug effects* / Q000502:physiology
chemical_list: D001993:Bronchodilator Agents; D011433:Propranolol; D000420:Albuterol
keywords: distribution; pharmacokinetics; pulmonary; pulmonary drug delivery; tissue partition