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.

Acyclovir prodrug for the intestinal di/tri-peptide transporter PEPT1: comparison of in vivo bioavailability in rats and transport in Caco-2 cells.

It has previously been shown that the prodrug Glu(acyclovir)-Sar has a high affinity for PEPT1 in Caco-2 cells. However, affinity does not necessarily lead to translocation by the transporter which is necessary for achieving an increased oral bioavailability. Therefore i.v. and p.o. doses of Glu(acyclovir)-Sar, acyclovir and valacyclovir were given to rats and the collected blood samples were analysed via LC-MS-MS. Furthermore, Caco-2 cell monolayers were exposed apically to Glu(acyclovir)-Sar, acyclovir, and valacyclovir and the concentration of drug and prodrugs in the cell extracts were determined and taken as a measure for intracellular accumulation. In addition, bi-directional transport studies of Glu(acyclovir)-Sar across Caco-2 cell monolayers and in vitro metabolism studies of Glu(acyclovir)-Sar in various media of rat origin were performed. For these purposes HPLC-UV analysis was applied. Oral administration of Glu(acyclovir)-Sar to rats resulted in low bioavailabilities of acyclovir (<2%) and intact prodrug (<5%). Studies performed on Caco-2 cell monolayers showed that in contrast to valacyclovir Glu(acyclovir)-Sar did not result in a detectable amount of acyclovir or Glu(acyclovir)-Sar in the cell extracts. Bi-directional flux across Caco-2 cell monolayers apical to basolateral (FluxA-->B) and basolateral to apical (FluxB-->A) was measured and the FluxB-->A/FluxA-->B ratios of approximately 0.8 indicate that apical efflux mechanisms may not explain this lack of intracellular accumulation. These data indicate that Glu(acyclovir)-Sar may not be translocated by PEPT1.