Possible Extraction of Drugs from Lung Tissue During Broncho-alveolar Lavage Suggest Uncertainty in the Procedure's Utility for Quantitative Assessment of Airway Drug Exposure

Uppsala universitet, Institutionen för farmaceutisk biovetenskap Uppsala universitet, Institutionen för farmaci AstraZeneca, BioPharmaceut R&D, Drug Metab & Pharmacokinet, Res & Early Dev,Resp & Immunol, Gothenburg, Sweden. AstraZeneca, BioPharmaceut R&D, Drug Metab & Pharmacokinet, Res & Early Dev,Resp & Immunol, Gothenburg, Sweden. AstraZeneca, BioPharmaceut R&D, Drug Metab & Pharmacokinet, Res & Early Dev,Resp & Immunol, Gothenburg, Sweden. AstraZeneca, BioPharmaceut R&D, Clin Pharmacol & Safety Sci, Clin Pharmacol & Quantitat Pharmacol, Gothenburg, Sweden. AstraZeneca, BioPharmaceut R&D, Drug Metab & Pharmacokinet, Res & Early Dev,Resp & Immunol, Gothenburg, Sweden. AstraZeneca, Inhalat Prod Dev, Pharmaceut Technol & Dev, Operat, Gothenburg, Sweden. AstraZeneca, BioPharmaceut R&D, Biosci COPD IPF, Res & Early Dev,Resp & Immunol, Gothenburg, Sweden. Elsevier BV 2022

Following inhaled dosing, broncho-alveolar lavage (BAL) is often used for sampling epithelial lining fluid (ELF) to determine drug concentration in the lungs. This study aimed to explore the technique's suitability. Urea is typically used to estimate the dilution factor between the BAL fluid and physiological ELF, since it readily permeates through all fluids in the body. As representatives of permeable small molecule drugs with high, medium and low tissue distribution properties, propranolol, diazepam, indomethacin and AZD4721 were infused intravenously to steady state to ensure equal unbound drug concentrations throughout the body. The results showed that propranolol had higher unbound concentrations in the ELF compared to the plasma whilst this was not the case for the other compounds. Experiments with different BAL volumes and repeated lavaging indicated that the amount of drug extracted is very sensitive to experimental procedure. In addition, the results show that the unbound concentrations in ELF compared to plasma differs dependent on molecule class and tissue distribution properties. Overall data suggests that lavaging can remove drug from lung tissue in addition to ELF and highlights significant uncertainty in the robustness of the procedure for determining ELF drug concentrations. (c) 2021 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.

Pulmonary drug delivery; Pharmacokinetics; Distribution; Protein binding; Tissue partition; Respiratory Medicine and Allergy; Lungmedicin och allergi; Article in journal; info:eu-repo/semantics/article; text

10.1016.j.xphs.2021.12.004

Open access content. Open access content

English

UPE oai:DiVA.org:uu-470574
doi:10.1016/j.xphs.2021.12.004
PMID 34890629
ISI:000766612400008
1312847275

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