Carrier mediated transport of chlorpheniramine and chlorcyclizine across bovine olfactory mucosa: Implications on nose‐to‐brain transport

Delivery to the CNS via the nasal cavity has been pursued as a means to circumvent the blood-brain barrier (BBB), yet the mechanism of drug transport across this novel route is not well understood. Hydroxyzine and triprolidine have been reported to readily reach the CNS following nasal administration, whereas no measurable amounts of chlorcyclizine or chlorpheniramine, structurally similar antihistamines, were observed in the CSF. The permeation of chlorpheniramine and chlorcyclizine in vitro across the bovine olfactory mucosa was studied to investigate the biological and physicochemical characteristics that contribute to the limited CNS disposition of these compounds following nasal administration. The submucosal to mucosal fluxes (Js-m) of chlorcyclizine and chlorpheniramine across the olfactory mucosa were significantly greater than the mucosal to submucosal fluxes (Jm-s). Moreover, the submucosal-mucosal permeability of both compounds was temperature dependent and saturable. In the presence of metabolic inhibitors (ouabain and 2,4‐dinitrophenol) and P‐glycoprotein (P‐gp)/multidrug resistance protein 1 (MRP1) inhibitors (quinidine and verapamil), the Jm-s increased and Js-m decreased significantly. These results indicate that chlorpheniramine and chlorcyclizine are effluxed from the olfactory mucosa by efflux transporters such as P‐gp and MRP1. Transport studies across inert polymeric membranes demonstrated that the permeability of chlorpheniramine and chlorcyclizine decreased at donor concentrations higher than 3 mM suggesting that physicochemical properties such as self‐aggregation also play a role in the reduced olfactory mucosal permeability of these compounds at higher concentrations. © 2005 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 94:613-624, 2005