Comparative pharmacokinetics of tetramethylpyrazine phosphate in rat plasma and extracellular fluid of brain after intranasal, intragastric and intravenous administration

The purpose of this study was to compare the pharmacokinetic profiles of tetramethylpyrazine phosphate (TMPP) in plasma and extracellular fluid of the cerebral cortex of rats via three delivery routes: intranasal (i.n.), intragastric (i.g.) and intravenous (i.v.) administration. After i.n., i.g. and i.v. administration of a single-dose at 10 mg/kg, cerebral cortex dialysates and plasma samples drawn from the carotid artery were collected at timed intervals. The concentration of TMPP in the samples was analyzed by HPLC. The area under the concentration–time curve (AUC) and the ratio of the AUC(brain) to the AUC(plasma) (drug targeting efficiency, DTE) was calculated to evaluate the brain targeting efficiency of the drug via these different routes of administration. After i.n. administration, TMPP was rapidly absorbed to reach its peak plasma concentration within 5 min and showed a delayed uptake into cerebral cortex (t(max)=15 min). The ratio of the AUC(brain dialysates) value between i.n. route and i.v. injection was 0.68, which was greater than that obtained after i.g. administration (0.43). The systemic bioavailability obtained with i.n. administration was greater than that obtained by the i.g. route (86.33% vs. 50.39%), whereas the DTE of the nasal route was 78.89%, close to that of oral administration (85.69%). These results indicate that TMPP is rapidly absorbed from the nasal mucosa into the systemic circulation, and then crosses the blood–brain barrier (BBB) to reach the cerebral cortex. Intranasal administration of TMPP could be a promising alternative to intravenous and oral approaches.