J Z Sun1, P R Byron, F Rypacek. 1. Aerosol Research Group, School of Pharmacy, Virginia Commonwealth University, Richmond 23298, USA.
Abstract
PURPOSE: To determine the effects of ionized substituents upon the pulmonary absorption of 6-8 kDa synthetic, hydrophilic polypeptides. METHODS: Fluorophore-labeled poly (hydroxyethylaspartamide), F-PHEA (neutral at pH 7.4) and its copolymer derivatives poly (hydroxyethylaspartamide-co-dimethylaminopropylaspartamide), F-P(HEA-DMAPA) (positive at pH 7.4) and poly (hydroxyethylaspartamide-co-aspartic acid), F-P(HEA-AA) (negative at pH 7.4) were synthesized and administered in different concentrations to the airways of the isolated rat lung preparation. The time and molecular weight dependencies of polypeptide absorption into perfusate were determined at intervals by gel permeation chromatography. RESULTS: For all polypeptides, molecular weights in perfusate were about 1 kDa less than those which were administered, due to preferential absorption of smaller molecules. The absorption, up to 70% of the administered dose over 3 h, of the anionic F-P(HEA-AA), was significantly faster than that of the neutral F-PHEA or the polycationic F-P(HEA-DMAPA). The latter derivative produced greatest edema in the lung. Absorption showed both active [dose-dependent kinetics] and passive [diffusive] components for all three polymers. CONCLUSIONS: Pulmonary absorption of similarly sized macromolecular PHEA derivatives, either neutral, positively or negatively charged, occured via carrier-mediated and diffusive mechanisms. The highest rate of absorption was observed with the polyanionic derivative.
PURPOSE: To determine the effects of ionized substituents upon the pulmonary absorption of 6-8 kDa synthetic, hydrophilic polypeptides. METHODS: Fluorophore-labeled poly (hydroxyethylaspartamide), F-PHEA (neutral at pH 7.4) and its copolymer derivatives poly (hydroxyethylaspartamide-co-dimethylaminopropylaspartamide), F-P(HEA-DMAPA) (positive at pH 7.4) and poly (hydroxyethylaspartamide-co-aspartic acid), F-P(HEA-AA) (negative at pH 7.4) were synthesized and administered in different concentrations to the airways of the isolated rat lung preparation. The time and molecular weight dependencies of polypeptide absorption into perfusate were determined at intervals by gel permeation chromatography. RESULTS: For all polypeptides, molecular weights in perfusate were about 1 kDa less than those which were administered, due to preferential absorption of smaller molecules. The absorption, up to 70% of the administered dose over 3 h, of the anionic F-P(HEA-AA), was significantly faster than that of the neutral F-PHEA or the polycationic F-P(HEA-DMAPA). The latter derivative produced greatest edema in the lung. Absorption showed both active [dose-dependent kinetics] and passive [diffusive] components for all three polymers. CONCLUSIONS: Pulmonary absorption of similarly sized macromolecular PHEA derivatives, either neutral, positively or negatively charged, occured via carrier-mediated and diffusive mechanisms. The highest rate of absorption was observed with the polyanionic derivative.