Pharmacokinetics Of Inhalation Aerosols Implications For Cancer Treatment

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The absorption and distribution of drug following deposition of the aerosol particles in the airways is a complex process. However, it is of paramount importance to understand the dynamics of drug fate in order to achieve optimal efficacy of chemotherapeutic agents. Much information on the fate of inhaled drugs has been obtained from asthma medications that have been investigated extensively (114), though recently a great amount of research on this topic has arisen due to the interest in using the lungs as a portal to the systemic circulation (115).

Time from start of treatment (hr)

Figure 3 Pharmacokinetics of liposomal 9-NC. Mean (+SD) plasma levels in five cancer patients following treatment with 9-NC liposome aerosol by mouth-only breathing. Source: From Ref. 60.

Time from start of treatment (hr)

Figure 3 Pharmacokinetics of liposomal 9-NC. Mean (+SD) plasma levels in five cancer patients following treatment with 9-NC liposome aerosol by mouth-only breathing. Source: From Ref. 60.

The airways sequentially branch into multiple generations (usually modeled with 23 generations of bifurcations) and the morphological and cellular changes along these dividing structures can lead to significantly altered absorption and clearance rates depending on deposition patterns. The airway surface epithelial monolayer is a columnar epithelium populated by many mucus and ciliated cells that collectively form the mucociliary escalator. This barrier gradually thins as the airways branch. Particles that deposit on this portion of the airways may be efficiently cleared by the mucociliary escalator that is present along the conducting airways. Insoluble particles that deposit in the airways are efficiently swept up and removed from the lungs on this moving carpet of mucus over a time period of several hours (116).

The epithelial monolayer that comprises the alveoli is very different from the epithelia of the conducting airways. Alveolar Type 1 cells are thin and flattened, covering approximately 95% of the alveolar surface. Alveolar macrophages are a key cell in the maintenance of lung homeostasis and reside in the alveolar region, where they detect, engulf, and digest any foreign particles that have eluded the aerodynamic filters of the upper respiratory passages. Together these clearance mechanisms are well adapted to eliminating particles from the lungs in a matter of hours. Surmounting these mechanisms is particularly challenging and only a few reports of sustained release pulmonary delivery are found in the literature (117,118).

If a drug that is deposited in the lungs is soluble in the fluid lining the airways, the efficiency of the aforementioned clearance mechanisms will be significantly reduced, if not abrogated entirely. However, in general, residence time of small molecules deposited in the lungs is brief due to their rapid absorption into the systemic circulation. This absorption of small molecules from the respiratory tract into the systemic circulation is considered the fastest of any route of delivery other than intravenous (119), and stems from the exceptionally large surface area (between 50 and 100 m2) of relatively high permeability epithelia and the highly dispersed nature of the drug dose as an aerosol. The resistance to systemic absorption of inhaled medicines from the airways appears to occur at the plasma membrane of the lung epithelium (120,121).

Absorption is dependent on both the location of drug deposition in the respiratory tract and the physicochemical nature of the drug. For example, small hydrophobic molecules are thought to be rapidly absorbed from the lungs regardless of deposition site via passive diffusion through the plasma membrane. Conversely, small hydrophilic molecules may be absorbed more slowly by specific transporters or across the tight junctions. The tightness of cell junctions, as measured by electrical resistance and conductivity, appears to decrease from a maximum value in the trachea to a minimum in the distal airways prior to once again increasing to a high value in the alveoli (122).

The distribution of pulmonary administered chemotherapy agents is important for clinical effectiveness. Thus, for practical purposes, chemotherapy absorption rates, lung residence time, and the potential for significant systemic exposure depend on the location of drug deposition and the physicochemical nature of the drug. Typical physicochemical properties of chemotherapeutics commonly employed for lung cancer chemotherapy generally possess low water solubility and high lipophilicity. For example, the octanol/water partition coefficient of paclitaxel is high (>100) and will therefore exhibit very rapid absorption from the lung. In fact, octanol/water partition coefficients greater than 100 generally lead to absorption half-lives of approximately 10min (123,124). Thus, it is possible that aerosol administration of highly permeating chemotherapeutic agents will not provide appropriate pharmacokinetics for sustained local delivery and treatment of lung tumors using immediate release aerosols. Optimal tumor cell exposure may be enhanced by sustaining the release of the cancer drug so that prolonged concentrations capture all cells in different stages of the cell cycle, reducing the rate of tumor cell repopulation, and increasing tumor penetration of the cytotoxic.

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  • abdullah
    How do the lungs have an exceptionally large surface area for drugs?
    7 months ago

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