Study on brain targeting of raltitrexed following intranasal administration in rats.

Purpose: To investigate the levels of raltitrexed (RTX) in blood and different brain tissues in rats and to find out whether there is any direct drug transport from nasal cavity to brain tissues following intranasal (i.n.) administration.

Methods: Raltitrexed was administered to male Sprague-Dawley rats either intranasally or intravenously. Drug concentrations in blood and brain tissues were determined at different times post dosing.

Results: The plasma levels achieved after i.n. administration were significantly lower than those following intravenous (i.v.) administration (P < 0.05) before 120 min; but were significantly higher (P < 0.05) after 120 min. Following i.n. administration, RTX concentrations in different brain tissues were constantly detected for quite a long time and differed significantly from each other, the rank order being C (OB) > C (OT) > C (CR) > C (CL). On the contrary, RTX appeared only at the initial two or three time points in different brain regions after i.v. injection, and the concentrations were similar. AUC values in four brain regions by the nasal route were 54- to 121-fold compared with the i.v. route, the drug targeting index (DTI) values of nasal route were 71-158 for different brain regions, and about 99% of RTX content within 360 min in the brain were transported via the olfactory pathway.

Conclusions: These results showed that antineoplastic RTX could be directly transported into the brain via the olfactory pathway in rats.