Novel strategies of aerosolic pharmacotherapy
Introduction
The aerosolic administration of drugs plays an important role in the treatment of pulmonary and systemic diseases and the unique cellular properties of airway epithelium offer a great potential to deliver new compounds (Groneberg et al., 2004a). Using aerosolized drugs diseases such as bronchial asthma (Rubin and Fink, 2001), chronic obstructive pulmonary disease (COPD) (Newhouse and Corkery, 2001), cystic fibrosis (Beringer, 1999), bacterial pneumonia (Wood and Boucher, 2000; Flume and Klepser, 2002) or viral respiratory infections (O’Riordan and Faris, 1999; Groneberg et al., 2003d, Groneberg et al., 2005b, Groneberg et al., 2005c) may be treated (Table 1). Also, non-respiratory diseases may be treated via the pulmonary route (Table 2).
As the relative contributions from the large airways to the alveolar space are important factors concerning the local and systemic availability of target compounds, the sites and mechanism of uptake and transport need to be known.
Among the different cells of the respiratory tract, the ciliated epithelial cells of the larger and smaller airways and the type I and type II pneumocytes are the key players in pulmonary transport of drugs (Groneberg et al., 2003c). They each have diverse cellular characteristics and offer unique uptake possibilities. Next to the importance of knowledge about the transport properties of each of these cells, the structure of aerosolized drugs, the characteristics of delivery systems and the deposition and pulmonary clearance display crucial factors in pulmonary drug delivery mechanisms.
Based on the growing knowledge on cell biology and pathophysiology due to modern methods of molecular biology such as gene depletion or overexpression (Kerzel et al., 2003; Springer et al., 2004c), the future characterization of pulmonary drug transport pathways can lead to new strategies in aerosol drug therapy.
Section snippets
Cellular and morphological aspects of drug transport
The transepithelial transport along the respiratory epithelium from the upper airways to the lower respiratory tract is characterized by large quantitative differences. In the upper airways the transport is limited by a smaller surface area and a lower regional blood flow. The upper airways also possess a high filtering capacity and can remove between 70% and 90% of pressurized particles while the smaller airways and the alveolar space account for more than 95% of the lung's total surface area (
Administration of drugs and deposition
There are two main modes of pulmonary drug administration: nasal or oral inhalation. The nasal inhalation is limited by anatomical features such as a narrower airway lumen. Therefore, the route of oral inhalation of compounds is generally preferred and previous studies demonstrated a better oral inhalative administration of 5 μm diameter particles with a concentration loss of only 20% in comparison to 85% by nasal administration (Lippmann and Albert, 1969; Lippmann et al., 1980). The three
Delivery devices
Although there are numerous devices that can be used for particle generation (Newman, 1991; Thompson, 1998) (Table 3), the most common systems are nebulizers, metered dose inhalers (MDIs), and dry powder inhalers (PDIs). The currently used standard inhalation devices produce aerosols which are heterodisperse in size. While monodisperse particle-sized aerosols are superior concerning targeted delivery to the lower airways, the production of these monodisperse particles is limited by complex and
Pulmonary drug transporter
The cDNAs encoding two families of proton-coupled oligopeptide transporters have been cloned from epithelial cells of intestine (PEPT1) and kidney cortex (PEPT2) (Daniel and Rubio-Aliaga, 2003). While PEPT1 is expressed in the intestine (Groneberg et al., 2001b) and to smaller extent in kidney (Daniel and Rubio-Aliaga, 2003) but not lung (Groneberg et al., 2001d), PEPT2 is expressed in the kidney (Groneberg et al., 2002a; Rubio-Aliaga et al., 2003), nervous system (Groneberg et al., 2001c,
Conclusion
Pulmonary drug administration plays a major role in the treatment of both respiratory and systemic diseases and is attractive for future drug development. The effects of aerosol-based drugs depend on multiple factors including the nature of the compounds, cellular aspects of transport and characteristics of delivery systems and aerosol administration. Thus, multiple ways to optimize drug delivery exist.
Concerning the cellular drug transport via drug transporters, future studies addressing the
Acknowledgements
This study was supported by the German Academic Exchange Service (DAAD, D/00/10559), and the German Research Community DFG (GR 2014/2-1).
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