Lack of a primary physicochemical determinant in the direct transport of drugs to the brain after nasal administration in rats: potential involvement of transporters in the pathway.

Summary: The objectives of this study were to evaluate the relative contribution of the direct pathway in overall brain transport for 17 model drugs with different physicochemical properties after nasal administrations and to identify factors that govern the fraction of the dose transported to the brain via the direct pathway (F a direct ). When the model drugs were nasally administered to rats, 5 of the 17 model drugs were delivered to a significant extent to the brain via the direct pathway. Multiple linear regression analyses showed that the correlation between various physicochemical properties and Fa, direct was not statistically significant, indicative of a lack of primary physicochemical determinants in the direct transport pathway. Transporters such as rOAT3 and rOCT2 were expressed at significant levels in rat olfactory epithelia, and uptakes of standard substrates were significantly decreased in HEK293 cells expressing rOAT3 and rOCT2 in the presence of the five model drugs that were delivered to appreciable extents to the brain via the direct pathway. Therefore, these observations indicate that carrier-mediated transport may play a role in the brain delivery of drugs from the nose via the direct transport pathway.