Nasal drug delivery to the cerebrospinal fluid: transport of a lipophilic compound

Abstract

The aim of this study was to investigate the possibility of direct transport of drugs from the olfactory area to the cerebrospinal fluid (CSF) by intranasal administration (i.n.) of a lipophilic drug in human volunteers. In a large number of animal studies evidence has been found for drug transport via the nose to the brain [1]. Human studies are suggesting such a transport, for instance for i.n. midazolam [2], on pharmacodynamic grounds, but pharmacokinetic evidence is as yet missing. This study evaluates drug CSF concentrations in patients at the neurosurgery department after i.n. and intravenous (i.v.) administration of melatonin, used in this study as a lipophilic model compound. It has been chosen because it is an endogenous relatively safe compound, for which a very good nasal absorption has been reported [3]. In a pharmacokinetic study, patients at the neurosurgery department with an external cerebrospinal drain were recruited. Three patients were included. Each patient received on one day melatonin i.n. as a dose of 400 μg (200 μg in each nostril) and on another day 200 μg melatonin i.v. Blood samples and CSF samples were collected just before and at 5, 10, 20, 0, 40, 60, 120 and 180 min after drug administration. Melatonin concentrations were measured with h.p.l.c. Concentration–time curves of the plasma and CSF concentrations of melatonin were compared after i.n. and i.v. administration. The nasal absorption of melatonin in blood is fast and efficient. Peak plasma concentrations after i.n. are reached within 20 min and are comparable with those reached after i.v. administration. The AUCCSF:AUCplasma after i.n. administration was in all three patients not larger than after i.v. administration. In the three investigated patients the increase in CSF melatonin concentration after i.n. administration appeared to be comparable with that after i.v. administration (Table 1). Table 1 AUC (0, 180 min) of melatonin in CSF after i.n. and i.v. administration. The increase of the melatonin concentrations in the CSF does not differ largely in the period 0–180 min, whether the drug is administered i.n. or i.v., indicating that the drug enters the CSF via the systemic circulation and the blood–brain barrier. It is evident that i.n. administration of a lipophilic compound could be an interesting alternative route of administration, giving high blood and also high CSF concentrations, but the results of this study provide no indication for an additional transport mechanism of the lipophilic compound directly from the nose to the CSF.