Alveolar macrophages are a primary barrier to pulmonary absorption of macromolecules.
We demonstrate that a primary source of elimination of inhaled macromolecules after delivery to the lungs and before absorption into the systemic circulation owes to clearance by alveolar macrophages (AM). Depletion of AM by liposome-encapsulated dichloromethylene diphosphonate is shown to cause severalfold enhancement in systemic absorption of IgG and human chorionic gonadotropin after intratracheal instillation in rats. Lowering the doses of IgG delivered to the lungs alleviates local degradation and results in a dramatic increase in systemic absorption of the protein as well. Chemical and physical means of minimizing uptake of macromolecules by AM are proposed as novel methods for enhancing protein absorption from the lungs. Such strategies may have important ramifications on the development of inhalation as an attractive mode of administration of therapeutic proteins to the bloodstream.
Lombry
Catherine
C
Dept. of Pharmaceutical Technology, School of Pharmacy, Université Catholique de Louvain, Ave. E. Mounier 73 UCL 73.20, 1200 Brussels, Belgium.
Edwards
David A
DA
Préat
Véronique
V
Vanbever
Rita
R
D000042:Absorption / Q000502:physiology; D000280:Administration, Inhalation; D000818:Animals; D004002:Clodronic Acid / Q000493:pharmacokinetics*; D004337:Drug Carriers; D016650:Fluorescein-5-isothiocyanate; D007074:Immunoglobulin G / Q000378:metabolism; D007322:Instillation, Drug; D008081:Liposomes; D008168:Lung / Q000166:cytology / Q000502:physiology*; D016676:Macrophages, Alveolar / Q000166:cytology / Q000502:physiology*; D008297:Male; D018613:Microscopy, Confocal; D051381:Rats; D017208:Rats, Wistar
D004337:Drug Carriers; D007074:Immunoglobulin G; D008081:Liposomes; D004002:Clodronic Acid; D016650:Fluorescein-5-isothiocyanate