The distribution of local anesthetics into the CSF following intranasal administration

The distribution of therapeutic agents into the CNS following nasal administration has been found to be highly compound dependent (Kumar et al., 1979, Recent Advances in Reproduction and Regulation of Fertility, Elsevier, Amsterdam, pp. 49-56; Hussain et al., 1990, J. Pharm. Sci., 79, 771-772; Chou and Donovan, 1997, Biopharm. Drug Dispos., 18, 335-346). In order to gain additional insight into the chemical specificity of transport between the nasal cavity and the CNS, a series of local anesthetics with similar chemical structures were used as model compounds to investigate drug disposition following intranasal administration. The selected local anesthetics were administered to male, Sprague-Dawley rats either intranasally or intra-arterially. Drug concentrations were determined from CSF and plasma samples collected from the cisterna magna and femoral artery, respectively. The plasma levels achieved after intranasal administration were comparable to those measured after the intra-arterial administration of an equivalent dose for three of the four compounds studied. Procaine, the compound with the lowest distribution coefficient, showed much lower plasma concentrations following intranasal administration. The relative bioavailability of procaine obtained following nasal administration was approximately 43% compared to 100% for the other selected local anesthetics. The ratios of the AUG,,, values obtained after nasal administration to those obtained after parenteral administration were found to be: tetracaine > bupivacaine > lidocaine > procaine. This rank order was well correlated to the distribution coefficients of the local anesthetics. Also of note, the AUC(CSF)/AUC(plasma) ratios of local anesthetics containing ester functionalities were much higher than for those containing amide linkages regardless of the route of administration. While the distribution of these compounds into the CSF followed the expected pattern based on a partitioning model, the time courses of drug concentrations within the CSF differed significantly depending both on the compound and the route of administration. (C) 1998 Elsevier Science B.V. All rights reserved.