Intrapulmonary Administration of Peptide Drugs In a Unique Rat Model: Increased Drug Absorption and Avoidance of "First Pass" Liver Clearance
Hoover, Jennifer Leigh
Peptide drugs represent an important therapeutic pharmaceutical class for the treatment of many chronic illnesses. Unfortunately, oral administration, the most favored delivery route, often results in extremely low absorption due to degradation in the gastrointestinal (GI) tract and frequent "first pass" liver clearance. The low bioavailability and biological activity, following oral administration, makes this route less than optimal for the delivery of peptide drugs. Therefore the intrapulmonary route was investigated. Synthetic model peptides, which varied systematically in molecular mass, hydrogen bond number, and lipophilicity were administered into the lungs to determine the factors which affect intrapulmonary absorption. The results suggest that the major determinant of gut absorption, hydrogen bond number, plays no significant role in absorption from the lung. Additional intrapulmonary administration studies were performed with two potential drug candidates, U77436, a renIn inhibitor and U75875, an HIV protease inhibitor. Each peptide exhibited "sustained release" over ten hours. All peptides exhibited greater than 50% absorption, suggesting that the intrapulmonary route is a promising alternative to oral peptide delivery.
XIII, 128 p.
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