Intrapulmonary Pharmacokinetics and Drug Distribution Characteristics for the Treatment of Respiratory Diseases

• Togami Kohei

  Faculty of Pharmaceutical Sciences, Hokkaido University of Science

Bibliographic Information

Other Title

• 呼吸器疾患治療のための薬物の肺内動態及び肺組織分布特性の解明
• Review for award 呼吸器疾患治療のための薬物の肺内動態及び肺組織分布特性の解明
• Review for award コキュウキ シッカン チリョウ ノ タメ ノ ヤクブツ ノ ハイ ナイ ドウタイ オヨビ ハイ ソシキ ブンプ トクセイ ノ カイメイ

Abstract

This study was designed to clarify the intrapulmonary pharmacokinetics and distribution characteristics of drugs in order to develop better therapies for respiratory diseases, including respiratory infections and pulmonary fibrosis. The distribution characteristics of three macrolide antimicrobial agents—clarithromycin, azithromycin, and telithromycin—in plasma, lung epithelial lining fluid (ELF), and alveolar macrophages (AMs), were examined for the optimization of antimicrobial therapy. The time course of the uptake of these agents in ELF and AMs, following oral administration to rats, resulted in markedly higher concentrations than that in plasma. The high concentration of the agents in AMs was due to their sustained distribution to ELF via multidrug resistance protein 1 and to high uptake by AMs themselves via active transport mechanisms and trapping and/or binding in acidic organelles. The intrapulmonary pharmacokinetics of aerosolized model compounds administered to animals with bleomycin-induced pulmonary fibrosis via aerosol formulations of model compounds (MicroSprayer) were then evaluated. The concentrations of these compounds in the plasma of pulmonary fibrotic rats were markedly higher than in that of control rats. The expression of epithelial tight junctions decreased in pulmonary fibrotic lesions. The accumulation of extracellular matrix inhibited the intrapulmonary distribution of aerosolized model compounds, indicating that aerosolized drugs are easily absorbed after leakage through damaged alveolar epithelia, but cannot become widely distributed in the lungs because of interruption by the extracellular matrix. This review provides useful findings for the development of therapies for respiratory infections and pulmonary fibrosis.

Journal

• YAKUGAKU ZASSHI

  YAKUGAKU ZASSHI 140 (3), 345-354, 2020-03-01

  The Pharmaceutical Society of Japan

Keywords

• respiratory infection
• macrolide antimicrobial agent
• lung epithelial fluid
• intrapulmonary administration
• idiopathic pulmonary fibrosis
• extracellular matrix

Details

• CRID: 1390283659855375872
• NII Article ID: 130007803976
• NII Book ID: AN00284903
• DOI: 10.1248/yakushi.19-00155
• ISSN: 13475231
• ISSN: 00316903
• NDL BIB ID: 030286462
• PubMed: 32115551
• Web Site: http://id.ndl.go.jp/bib/030286462
• Web Site: https://ndlsearch.ndl.go.jp/books/R000000004-I030286462
• Web Site: https://www.jstage.jst.go.jp/article/yakushi/140/3/140_19-00155/_pdf
• Web Site: https://search.jamas.or.jp/link/ui/2020186480
• Text Lang: ja
• Data Source:
  • JaLC
  • NDL
  • Crossref
  • PubMed
  • CiNii Articles
  • KAKEN
• Abstract License Flag: Disallowed