{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T12:54:48Z","timestamp":1777467288007,"version":"3.51.4"},"reference-count":59,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2020,4,29]],"date-time":"2020-04-29T00:00:00Z","timestamp":1588118400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/pharmaceutics12050408","type":"journal-article","created":{"date-parts":[[2020,4,29]],"date-time":"2020-04-29T13:23:45Z","timestamp":1588166625000},"page":"408","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Towards a Quantitative Mechanistic Understanding of Localized Pulmonary Tissue Retention\u2014A Combined In Vivo\/In Silico Approach Based on Four Model Drugs"],"prefix":"10.3390","volume":"12","author":[{"given":"Anneke","family":"Himstedt","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacy, Institute of Pharmacy, University of Hamburg, 20146 Hamburg, Germany"},{"name":"Drug Discovery Sciences, Boehringer Ingelheim Pharma GmbH &amp; Co. KG, 88397 Biberach, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Clemens","family":"Braun","sequence":"additional","affiliation":[{"name":"Drug Discovery Sciences, Boehringer Ingelheim Pharma GmbH &amp; Co. KG, 88397 Biberach, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sebastian Georg","family":"Wicha","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, Institute of Pharmacy, University of Hamburg, 20146 Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7000-9308","authenticated-orcid":false,"given":"Jens Markus","family":"Borghardt","sequence":"additional","affiliation":[{"name":"Drug Discovery Sciences, Boehringer Ingelheim Pharma GmbH &amp; Co. KG, 88397 Biberach, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,4,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S36","DOI":"10.1016\/S0091-6749(98)70004-1","article-title":"Establishing a therapeutic index for the inhaled corticosteroids: Part i: Pharmacokinetic\/pharmacodynamic comparison of the inhaled corticosteroids","volume":"102","author":"Kelly","year":"1998","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1016\/j.ejps.2009.10.001","article-title":"Lipid membrane interactions of indacaterol and salmeterol: Do they influence their pharmacological properties?","volume":"38","author":"Lombardi","year":"2009","journal-title":"Eur. J. Pharm. 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