Drug delivery to the brain after intranasal administration: The role of P-glycoprotein

Nasal administration has been explored as a means to deliver agents to the central nervous system (CNS). However, the mechanisms involved in brain uptake of substrates after nasal instillation are not well understood. Previous literature has suggested that nasal administration circumvents the blood-brain barrier (BBB). However, it appears that efflux transporters typically found at the BBB may influence brain penetration after nasal administration. P-glycoprotein (P-gp) is a BBB efflux transporter that limits brain uptake of numerous therapeutic agents. The objective of this dissertation research was to elucidate the role of P-gp in attenuating delivery of substrates to the brain after nasal administration in mice, and to explore the potential for targeted BBB P-gp modulation via nasal delivery. Experiments in P-gp-competent and P-gp-deficient animals revealed that P-gp attenuates brain uptake of nasally-delivered substrates in the same manner as with systemically-administered substrates. Furthermore, immunohistochemical studies indicated that P-gp was localized in endothelial cells that line the olfactory bulb, and in the olfactory epithelium. Fresh tissue slicing was conducted to explore the brain distribution of compounds (diazepam, verapamil, antipyrine and sucrose) in the absence of transport-mediated flux. Brain uptake of these model compounds was governed by lipophilicity, with more lipophilic compounds exhibiting higher total brain uptake. Pharmacokinetic modeling of these data supported the conclusion that lipophilicity governs brain uptake and disposition in the absence of transporter-mediated flux. Modeling also was consistent with P-gp localization at the olfactory epithelium, and indicated that P-gp is an important determinant of substrate distribution within brain. Utilizing nasal administration to deliver modulators to the brain appeared to allow more selective BBB P-gp modulation. Inhibition of BBB P-gp by rifampin was similar regardless of the route (nasal vs. systemic) of rifampin administration, but the nasal route achieved inhibition at an ∼400-fold lower dose. Pharmacodynamic studies utilizing loperamide indicated that P-gp modulation via nasal delivery achieves a pharmacologically relevant spectrum of P-gp inhibition. Taken together, these studies indicate that nasal delivery has the potential for targeted BBB delivery of P-gp modulators, allowing for increased brain penetration of agents that are excluded from brain based on their affinity for this transporter.