Crucial Biopharmaceutical Issues Facing Macromolecular Candidates for Inhalation: The Role of Macrophages in Pulmonary Protein Clearance
(2007) Respiratory Drug Delivery Europe — Vol. 2007, n° on-line publication, p. 31-42 (2007)
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- Our laboratory recently demonstrated that alveolar macrophages (AM) comprised a major barrier to the transport of two large proteins, IgG and human chorionic gonadotropin, from the airways into the bloodstream, while they had no impact on the peptide insulin. This study was aimed at assessing the role of AM in the alveolar clearance of human growth hormone (hGH), a smaller therapeutic protein being investigated as an inhalation aerosol in clinical trials. Using intratracheal instillation of liposome-encapsulated clodronate to deplete AM of rat lungs, we studied the pulmonary absorption of hGH in AM-depleted versus normal animals. The systemic absorption of hGH, following pulmonary administration, did not show significant alterations following AM depletion; absolute bioavailabilities reached 11.4%, 10.7% and 9.0% in clodronate liposome-, PBS liposome- and PBS-treated rats. Absorption from the lungs was rapid in all tested conditions, indicating that hGH crossed the alveolar epithelium quickly, presumably preventing major uptake and degradation by AM. AM uptake of proteins appears to be a significant local elimination mechanism for proteins above a certain size which implies a residence time within the alveolar spaces long enough for significant AM endocytosis.
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Ducreux, J., & Vanbever, R. (2007). Crucial Biopharmaceutical Issues Facing Macromolecular Candidates for Inhalation: The Role of Macrophages in Pulmonary Protein Clearance. Respiratory Drug Delivery Europe, 2007(on-line publication), 31-42. https://hdl.handle.net/2078.5/240626 (Original work published 2007)