Bypassing P-Glycoprotein Drug Efflux Mechanisms: Possible Applications in Pharmacoresistant Schizophrenia Therapy

Abstract

The efficient noninvasive treatment of neurodegenerative disorders is often constrained by reduced permeation of therapeutic agents into the central nervous system (CNS). A vast majority of bioactive agents do not readily permeate into the brain tissue due to the existence of the blood-brain barrier (BBB) and the associated P-glycoprotein efflux transporter. The overexpression of the MDR1 P-glycoprotein has been related to the occurrence of multidrug resistance in CNS diseases. Various research outputs have focused on overcoming the P-glycoprotein drug efflux transporter, which mainly involve its inhibition or bypassing mechanisms. Studies into neurodegenerative disorders have shown that the P-glycoprotein efflux transporter plays a vital role in the progression of schizophrenia, with a noted increase in P-glycoprotein function among schizophrenic patients, thereby reducing therapeutic outcomes. In this review, we address the hypothesis that methods employed in overcoming P-glycoprotein in cancer and other disease states at the level of the BBB and intestine may be applied to schizophrenia drug delivery system design to improve clinical efficiency of drug therapies. In addition, the current review explores polymers and drug delivery systems capable of P-gp inhibition and modulation.

Figure 1

(a) Description of the aetiological complexity of schizophrenia [14] (reproduced with permission from Macmillan Publishers Ltd. Nature 2010). (b) Stages of schizophrenia progression [23] (reproduced with permission from Elsevier B.V. Ltd. © 2009).

Figure 2

Drug Efflux by P-glycoprotein in the intestine [115] (reproduced with permission from Elsevier B.V. Ltd. © 2013).

Figure 3

Schematic representation of the cross section of the BBB cerebral capillary [116] (reproduced with permission from Elsevier B.V. Ltd. © 2007).

Figure 4

Respective locations of the drug efflux proteins on brain capillary endothelial cells that collectively form the BBB [35] (reproduced with permission from Elsevier B.V. Ltd. © 2005).

Figure 5

(a) Structural configuration of P-gp, MRP, and BCRP [47] (reproduced with permission from Elsevier B.V. Ltd. © 2005). (b) Diagrammatic representations of the “Vacuum Cleaner” and Flippase model of P-gp function [48] (reproduced with permission from Frontiers in Oncology Ltd. 2014).

Figure 6

Mechanism of inhibition of the P-gp efflux pump [117] (reproduced with permission from Elsevier B.V Ltd. © 2013).

Figure 7

TEM images of lipid based nanoparticles; arrows show the lipid bilayer thickness [87] (reproduced with permission from Elsevier B.V. Ltd. © 2013).

Figure 8

TEM micrographs showing the surface morphology of drug loaded micelles [91] (reproduced with permission from Elsevier B.V. Ltd. © 2011).

Figure 9

(a) (A) P-gp interacts with substrates in the plasma membrane and digoxin (substrate) is effluxed from the lipid bi-layer. (B) Cellular uptake of digoxin facilitated by Immunoliposomes-targeted to transferrin receptor and taken up via receptor-mediated endocytosis [94] (reproduced with permission from Drug Targeting Ltd. 2002). (b) (A) 2D Schematic representation of a dendrimer. (B) 3D representation of a dendrimer [100] (reproduced with permission from Elsevier B.V. Ltd. © 2009).