The blood-ocular barriers (BOB) make drug delivery to the ocular tissues, through the systemic route, a challenging task. The role of efflux proteins, such as P-glycoprotein (P-gp) and multidrug resistant proteins (MRPs), as major components of the BOB has already been well established in vitro. However, studies investigating their clinical implication, with respect to blood to eye penetration of substrates, have not been reported as yet. An understanding of the in vivo barrier characteristics of P-gp and MRP and development of noninvasive strategies to overcome efflux mediated by them, at the BOB, could improve ocular drug delivery through the systemic route. This would help avoid the drawbacks associated with direct intravitreal administration. This proposal is based on the novel hypothesis that the functional activity of the ocular efflux pumps can be significantly blocked through topical co-administration of inhibitors and will thus enhance the blood to eye penetration of efflux protein substrates. The feasibility of this approach has been demonstrated in our exploratory studies using rabbits as the animal model. In the current application we propose to evaluate, for the first time, the magnitude of the barrier properties of the ocular efflux proteins (P-gp and mrp1) in vivo in wild type and in P-gp and mrp1 knockout rats. The proposal also seeks to further elucidate the various facets of the novel strategy of localized inhibition of the efflux proteins expressed o the BOB with respect to extent and duration of inhibition and effect of topical formulation components. The effectiveness of the topical route will be compared to the systemic route of inhibitor administration, an approach commonly used to block efflux proteins on the blood-brain barrier. Thus, the specific aims of this project are to: (a) evaluate the magnitude of the ocular efflux protein barrier with respect to the systemic route of drug administration using P-gp (mdr1a) and mrp1 knockout and wild type rats, (b) establish the effectiveness of inhibiting the ocular efflux proteins through systemic inhibitor co-administration and (c) delineate the efficiency of the topical route of inhibitor application compared to the systemic route. Results from these studies will provide a deeper insight into the barrier properties of the ocular efflux pumps in vivo. It is expected that topical application of the inhibitors will lead to significantly enhanced ocular tissue concentrations of the systemically administered efflux protein substrates. This will open up the possibility of effectively treating ocular conditions such as endophthalmitis, uveitis and intraocular tumors through the systemic route. It may also provide a means to overcome the drug resistance encountered in some intraocular bacterial infections and ocular tumors, since the topically administered inhibitors may also block the multidrug resistant proteins up-regulated in these cells. It is thus expected that the results from these studies will provide new scientific insights into ocular drug delivery and improve therapeutic options and outcomes.
The studies proposed in this application will delineate, in vivo, the barrier characteristics of the ocular efflux proteins, P-glycoprotein (P-gp) and multidrug resistance proteins (MRP), and explore a novel noninvasive strategy for localized inhibition of their efflux activity at the blood-ocular barriers (BOB). This will help understand the clinical significance of these efflux mechanisms at the BOB and could lead to the generation and/or maintenance of enhanced drug concentrations in the ocular tissues through the systemic route. Results from this research project could thus improve treatment outcomes for ocular diseases such as endophthalmitis, intraocular tumors and uveitis.
