The lungs as a portal of entry for systemic drug delivery.
The lung is naturally permeable to all small-molecule drugs studied and to many therapeutic peptides and proteins. Absorption can be estimated using a simple animal test, intratracheal instillation. Inhalation offers a noninvasive route for the delivery of peptides and proteins that otherwise must be injected. Peptides that have been chemically altered to inhibit peptidase enzymes exhibit very high bioavailabilities by the pulmonary route. Natural mammalian peptides, less than about 30 amino acids, are broken down in the lung by ubiquitous peptidases and have very poor bioavailabilities. In general, proteins with molecular weights between 6,000 and 50,000 D are relatively resistant to most peptidases and have good bioavailabilities following inhalation. For larger proteins the bioavailability picture is not clear. Although the lung is rich in antiproteases, aggregation of inhaled proteins will stimulate opsonization (coating) by special proteins in the lung lining fluids, which will then mark the aggregated proteins for phagocytosis and intracellular enzymatic destruction. Small peptides and proteins are absorbed more rapidly after inhalation than after subcutaneous injection. For other small molecules, inhalation is also a fast way to get into the body because drug efflux transporters and metabolizing enzymes are present in the lung at much lower levels than the gastrointestinal tract. Lipophilic small molecules are absorbed extremely fast, t(1/2) (abs) approximately 1 to 2 minutes. Water-soluble small molecules are absorbed rapidly t(1/2) (abs) approximately 65 minutes. Small molecules can exhibit prolonged absorption if they are highly insoluble or highly cationic. Encapsulation in slow release particles such as liposomes can also be used to control absorption.
Patton
John S
JS
Nektar Therapeutics, Research Department, 150 Industrial Road, San Carlos, CA 94070, USA. jpatton@ca.nektar.com
Fishburn
C Simone
CS
Weers
Jeffry G
JG
D000280:Administration, Inhalation; D000336:Aerosols / Q000008:administration & dosage*; D000818:Animals; D001682:Biological Availability; D002986:Clinical Trials as Topic; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D006801:Humans; D008168:Lung / Q000187:drug effects*; D008970:Molecular Weight; D010316:Particle Size; D004364:Pharmaceutical Preparations / Q000008:administration & dosage*; D012680:Sensitivity and Specificity
D000336:Aerosols; D004364:Pharmaceutical Preparations