P-glycoprotein attenuates brain uptake of substrates after nasal instillation

Purpose. Previous literature has suggested the absence of an effective barrier between the nasal mucosa and the brain for compounds administered via the nasal route. These experiments were conducted to elucidate the role of the blood-brain barrier efflux transporter P-glycoprotein (P-gp) in attenuating delivery of P-gp substrates to the brain after nasal administration in mice. Methods. Brain uptake of several radiolabeled P-gp substrates, was measured in P-gp-deficient and P-gp-competent mice following nasal instillation. Additional experiments were performed to assess the potential for enhancing brain uptake by inhibiting P-gp with intranasal rifampin. Results. All substrates examined were measurable in brain tissue within 2 min. Substrate accumulation in P-gp-deficient mice was higher than in P-gp-competent animals; the degree to which P-gp attenuated brain uptake after nasal administration was similar to that during in situ brain perfusion. Co-administration of rifampin enhanced brain uptake of relevant substrates, and resulted in complete elimination of P-gp-mediated transport for H-3-verapamil. Conclusions. P-gp attenuates brain accumulation of intranasally-administered P-gp substrates. Thus, biochemical components of the blood-brain barrier, such as efflux transporters may influence brain penetration after nasal administration. Co-administration of a P-gp inhibitor enhances the brain uptake of relevant substrates, suggesting that the transporter barrier functions may be reversible.