Evaluation of direct transport pathways of glycine receptor antagonists and an angiotensin antagonist from the nasal cavity to the central nervous system in the rat model.
OBJECTIVE
The aim of this study was to investigate and quantify drug movement to the brain via the neuro-olfactory system after intranasal dosing of four model drugs; three glycine receptor antagonists and one angiotensin antagonist.


METHODS
The drugs were dosed to rats via intranasal or intravenous administration, after which a quantitative method for tissue distribution was utilised to determine drug distribution to the olfactory lobes, brain sections and the blood over 30 min. Autoradiography was used to visualise and quantify drug distribution throughout the brain and in the CSF. Micro-autoradiography was used to examine drug distribution throughout the olfactory nerve apparatus.


RESULTS
The three glycine receptor antagonist compounds were transported to the CNS to differing degrees although they had similar molecular structures and similar physicochemical characteristics. All three compounds were shown to exploit a direct route of transport from nose to brain with Direct Transport Percentages (DTP) of 99.99%, 96.71% and 51.95%, respectively, although for the last molecule a major part of the brain content originated from systemic transport across the BBB. Intranasal administration of GR138950 resulted in over 3.5 times more drug in the olfactory lobes at 1 min post-dose compared to intravenous administration; and 5 times more drug was delivered to the olfactory lobes over 30 min. Micro-autoradiography showed that GR138950 could be found throughout the olfactory nerve apparatus. Autoradiography illustrated drug distribution throughout the brain and CSF, with drug concentrations in the CSF being equal or higher than in the brain tissue. It was determined that approximately 0.8% of the administered dose moved into the brain and CSF via the olfactory pathway over 30 min.


CONCLUSIONS
Intranasal administration resulted in greater delivery of the model drugs to the olfactory lobes and brain as compared to intravenous dosing. It is proposed that the drug moved through the neuro-olfactory system, primarily via paracellular pathways.
Charlton
Stuart T
ST
The School of Pharmacy, University of Nottingham, University Park, Nottingham NG72RD, UK.
Whetstone
Joanne
J
Fayinka
Susan T
ST
Read
Kevin D
KD
Illum
Lisbeth
L
Davis
Stanley S
SS
D000281:Administration, Intranasal; D000809:Angiotensins / Q000037:antagonists & inhibitors*; D000818:Animals; D019540:Area Under Curve; D001345:Autoradiography; D001682:Biological Availability; D001693:Biological Transport, Active; D001921:Brain / Q000378:metabolism; D002490:Central Nervous System / Q000378:metabolism*; D002853:Chromatography, Liquid; D007275:Injections, Intravenous; D008297:Male; D013058:Mass Spectrometry; D009296:Nasal Cavity / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D018009:Receptors, Glycine / Q000037:antagonists & inhibitors*; D014018:Tissue Distribution
D000809:Angiotensins; D018009:Receptors, Glycine