A Comparison of the Pharmacokinetics and Pulmonary Lymphatic Exposure of a Generation 4 PEGylated Dendrimer Following Intravenous and Aerosol Administration to Rats and Sheep.
OBJECTIVE
Cancer metastasis to pulmonary lymph nodes dictates the need to deliver chemotherapeutic and diagnostic agents to the lung and associated lymph nodes. Drug conjugation to dendrimer-based delivery systems has the potential to reduce toxicity, enhance lung retention and promote lymphatic distribution in rats. The current study therefore evaluated the pharmacokinetics and lung lymphatic exposure of a PEGylated dendrimer following inhaled administration.


METHODS
Plasma pharmacokinetics and disposition of a 22 kDa PEGylated dendrimer were compared after aerosol administration to rats and sheep. Lung-derived lymph could not be sampled in rats and so lymphatic transport of the dendrimer from the lung was assessed in sheep.


RESULTS
Higher plasma concentrations were achieved when dendrimer was administered to the lungs of rats as a liquid instillation when compared to an aerosol. Plasma pharmacokinetics were similar between sheep and rats, although some differences in disposition patterns were evident. Unexpectedly, less than 0.5% of the aerosol dose was recovered in pulmonary lymph.


CONCLUSIONS
The data suggest that rats provide a relevant model for assessing the pharmacokinetics of inhaled macromolecules prior to evaluation in larger animals, but that the pulmonary lymphatics are unlikely to play a major role in the absorption of nanocarriers from the lungs.
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Pde, Parkville, VIC, 3052, Australia.
Gemma M
GM
Ryan
Biotechnology Research Laboratories, School of Biomedical Sciences, Monash University, Clayton, VIC, 3800, Australia.
Robert J
RJ
Bischof
Department of Anaesthesiology, University of Texas Medical Branch, 301 University Boulevard, Galveston, Texas, 77555, USA.
Perenlei
P
Enkhbaatar
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Pde, Parkville, VIC, 3052, Australia.
Victoria M
VM
McLeod
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Pde, Parkville, VIC, 3052, Australia.
Linda J
LJ
Chan
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Pde, Parkville, VIC, 3052, Australia.|Starpharma Pty Ltd, 4/6 Southhampton Cresent, Abbotsford, VIC, 3067, Australia.
Seth A
SA
Jones
Starpharma Pty Ltd, 4/6 Southhampton Cresent, Abbotsford, VIC, 3067, Australia.
David J
DJ
Owen
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Pde, Parkville, VIC, 3052, Australia.
Christopher J H
CJ
Porter
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Pde, Parkville, VIC, 3052, Australia. lisa.kaminskas@monash.edu.
Lisa M
LM
Kaminskas
D000280:Administration, Inhalation; D061605:Administration, Intravenous; D000336:Aerosols / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D000818:Animals; D050091:Dendrimers / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D016503:Drug Delivery Systems; D005260:Female; D008168:Lung / Q000378:metabolism*; D008198:Lymph Nodes / Q000378:metabolism*; D008297:Male; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012756:Sheep
D000336:Aerosols; D050091:Dendrimers; D004337:Drug Carriers; D011092:Polyethylene Glycols
lymphatic; pharmacokinetics; pulmonary; rats; sheep