The potential of nasal application for delivery to the central brain-a microdialysis study of fluorescein in rats.
Previous animal studies have shown that various types of nasally administered drugs and model substances can access the central nervous system (CNS) via direct transport across the olfactory epithelium, and thereby circumventing the blood-brain barrier (BBB). These compounds, however, have mainly been identified in the cerebrospinal fluid and the olfactory bulbs which are usually not pharmacologically relevant targets. The aim of the present study was to evaluate the potential of targeting the central brain by olfactory absorption by use of sodium fluorescein as a hydrophilic model substance with limited permeability across the blood-brain barrier. Microdialysis probes were implanted in blood and in right and left side of the brain (striatum) in rats. The pharmacokinetics of sodium fluorescein was studied from 0 to 180min following intravenous and unilateral nasal administration without occlusion of the oesophagus. Pharmacokinetic modelling showed a significantly higher absorption rate and lower T(max) in the ipsilateral striatum (0.097min(-1) and 41min) compared with the contralateral side (0.056min(-1) and 54min). The rate of elimination in brain was significantly lower after nasal administration (0.004min(-1)) compared with intravenous administration (0.012min(-1)). However, the brain to plasma area under the curve ratios of model substance were low (2-3%) and not significantly different between right and left side of the brain, regardless of the route of administration. The results obtained by microdialysis were supported by findings in whole brain homogenates where concentrations of fluorescein were approximately 40% higher in the right striatum compared with the left side initially after nasal administration to the right nostril of rats. Despite some indications of olfactory transport to the central rat brain it was concluded that the drug targeting potential of sodium fluorescein and most likely other hydrophilic compounds is limited.
Bagger
Morten Aavad
MA
Department of Pharmaceutics, The Danish University of Pharmaceutical Sciences, Universitetsparken 2, DK-2100, Copenhagen, Denmark. eb@dfh.dk
Bechgaard
Erik
E
D000281:Administration, Intranasal; D000818:Animals; D001682:Biological Availability; D001812:Blood-Brain Barrier / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D003287:Contrast Media / Q000008:administration & dosage / Q000493:pharmacokinetics*; D003342:Corpus Striatum / Q000378:metabolism*; D019793:Fluorescein / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D008297:Male; D017551:Microdialysis; D008954:Models, Biological; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D003287:Contrast Media; D019793:Fluorescein