1. J Aerosol Med Pulm Drug Deliv. 2010 Dec;23 Suppl 2:S71-87.

The particle has landed--characterizing the fate of inhaled pharmaceuticals.

Patton JS, Brain JD, Davies LA, Fiegel J, Gumbleton M, Kim KJ, Sakagami M,
Vanbever R, Ehrhardt C.

Dance Pharmaceuticals, San Francisco, California 94103, USA.
jpatton@dancepharma.com

Although there is a modest body of literature on the absorption of inhaled
pharmaceuticals by normal lungs and some limited information from diseased lungs,
there is still a surprising lack of mechanistic knowledge about the details of
the processes involved. Where are molecules absorbed, what mechanisms are
involved, how well are different lung regions penetrated, what are the
determinants of metabolism and dissolution, and how best can one retard the
clearance of molecules deposited in the lung or induce intracellular uptake by
lung cells? Some general principles are evident: (1) small hydrophobic molecules 
are absorbed very fast (within tens of seconds) usually with little metabolism;
(2) small hydrophilic molecules are absorbed fast (within tens of minutes), again
with minimal metabolism; (3) very low water solubility of the drug can retard
absorption; (4) peptides are rapidly absorbed but are significantly metabolized
unless chemically protected against peptidases; (5) larger proteins are more
slowly absorbed with variable bioavailabilities; and 6) insulin seems to be best 
absorbed distally in the lungs while certain antibodies appear to be
preferentially absorbed in the upper airways. For local lung disease
applications, and some systemic applications as well, many small molecules are
absorbed much too fast for convenient and effective therapies. For systemic
delivery of peptides and proteins, absorption may sometimes be too fast.
Bioavailabilities are often too low for cost-effective and reliable treatments. A
better understanding of the determinants of pulmonary drug dissolution,
absorption, metabolism, and how to target specific regions and/or cells in the
lung will enable safer and more effective inhaled medicines in the future.


PMID: 21133802 [PubMed - in process]