DO INTERACTIONS WITH PHOSPHOLIPIDS CONTRIBUTE TO THE PROLONGED RETENTION OF POLYPEPTIDES WITHIN THE LUNG

Several amphipathic or hydrophobic polypeptides exhibited prolonged re tention in the lung following pulmonary administrations. The physicoch emical basis for prolonged retention remains uncertain but may be rela ted to hydrophobic and electrostatic interactions between the polypept ides and the phospholipids of lung tissues. The pulmonary absorption c haracteristics of detirelix, polymyxin B, and cyclosporin A were revie wed in relation to their interactions with phospholipids. Phospholipid interactions were evaluated qualitatively by comparison of the effici encies of polypeptides' incorporation into liposomes, and by a quantit ative comparison of the polypeptide affinities for immobilized artific ial membranes (IAM). Detirelix and cyclosporin A exhibited prolonged p ulmonary retention compared with polymyxin B. Those observations corre lated with the polypeptides' liposomal incorporation efficiencies and IAM affinities. The duration of absorption of all three polypeptides w as further extended following pulmonary administration of their liposo mal formulations. A fourth polypeptide, lipopeptide L-693,989, was ide ntified as possessing the structural hydrophobicity sufficient to inte ract strongly with phospholipid bilayers: a possible explanation for i ts prolonged pulmonary retention.