Nasal Administration of Compounds Active in the Central Nervous System Exploring the Olfactory Pathway

Dahlin, M. 2000. Nasal Administration of Compounds Active in the Central Nervous System. Exploring the Olfactory Pathway. Acta Universitatits Uppsaliensis. Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy 240. 48 pp. Uppsala. ISBN 91-554-4872-0. The nasal administration of drugs offers advantages over administration by intravenous injection. Drugs can be rapidly absorbed through the nasal mucosa, resulting in a rapid onset of action, and also avoiding degradation in the gastrointestinal tract and first-pass metabolism in the liver. Targeting the brain via nasal administration offers potential for the development of new drugs. The olfactory receptor cells are in direct contact with both the environment and the central nervous system (CNS). The olfactory pathway thus circumvents the blood brain barrier (BBB) which prevents many systemically administered drugs from entering the brain. The studies used compounds active in the CNS and the experiments were performed in rodents. The nasal bioavailability of (S)-UH-301, NXX-066 and [H]-dopamine was investigated in a rat model; uptake into the cerebrospinal fluid (CSF) was compared after nasal and intravenous administration. The concentrations of (S)-UH-301 and NXX-066 in plasma and CSF were measured with high performance liquid chromatography. The possible transfer of dopamine and neurotensin along the olfactory pathway after nasal administration to mice was studied using brain tissue sampling and autoradiography. The radioactivity content in blood, CSF and dissected brain tissue samples after administration of [H]dopamine and [H]-neurotensin was assessed using liquid scintillation, and thin layer chromatography (TLC) was used to investigate the metabolic fate of [H]-dopamine. The results of this thesis suggest that nasal administration of CNS-active compounds with low oral bioavailability is an interesting and workable alternative to intravenous injection. The small lipophilic compounds (S)-UH-301 and NXX-066 were rapidly and completely absorbed after nasal administration, although hard evidence of direct transfer from the nose remains elusive. Radioactivity measurements in the olfactory bulb following nasal administration of [H]-dopamine and [H]-neurotensin indicate that some transfer occurred. The TLC results showed the presence of unchanged dopamine in the olfactory bulb but it is less clear from initial results with neurotensin which radioactive products of this molecule reached the olfactory bulb, and further studies are required. Maria Dahlin, Department of Pharmacy, Division of Pharmaceutics, Uppsala Biomedical Centre, Box 580, SE-751 23 Uppsala, Sweden