Transporter effects on cell permeability in drug delivery

ABSTRACT

Introduction: The role of drug transporters as one of the determinants of cellular drug permeability has become increasingly evident. Despite the lipophilicity of a drug molecule as rate-limiting factor for passive diffusion across biological membranes, carrier-mediated and active transport have gained attention over the years. A better understanding of the effects and roles of these influx transporters towards transmembrane permeability of a drug molecule need to be delineated for drug development and delivery.

Areas covered: This review focuses on findings relative to role of transporters in drug absorption and bioavailability. Particularly the areas demanding further research have been emphasized. This review will also highlight various transporters expressed on vital organs and their effects on drug pharmacokinetics.

Expert opinion: Significant efforts have been devoted to understand the role of transporters, their iterative interplay with metabolizing enzymes through molecular enzymology, binding and structure-activity relationship studies. A few assays such as parallel artificial membrane permeation assay (PAMPA) have been developed to analyze drug transport across phospholipid membranes. Although large web-accessible databases on tissue selective expression profiles at transcriptomic as well as proteomic are available, there is a need to collocate the scattered literature on the role of transporters in drug development and delivery.

KEYWORDS:

• Pathways
• gene
• influx
• efflux
• P-gp
• MRP
• BCRP
• ocular tissues
• BDDCS
• cancer

Article highlights

• The role of drug transporters as one of the determinants of cellular drug permeability has become increasingly evident in recent years.

• Transporter expression, particularly in epithelia of intestine, liver and kidney as well as endothelium of blood-brain barrier are the major determinants of cell permeability which consequently impacts drug pharmacokinetics.

• The ITC has implemented regulatory guidelines and other frameworks to build a custom drug transport strategy based on clinical data and therapeutic area.

• Decision trees with flexibility in its interpretation has been proposed and are being developed under the supervision of academic as well as regulatory agencies and industrial scientists to ensure the development of safe drugs.

• Molecular biology techniques such as gene silencing, cloning, RNA interference (RNAi) might prove to be more reliable than traditional methods in establishing direct correlations between the extent of drug accumulation and expression of transporters in a specific tissue.

• System biology strategies utilizing interplay between wet experiments, in silico modeling and technology development are being employed for establishing and delineating the roles of transporters in human drug transport systems.

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Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This work was supported by the U.S. Department of Health and Human Services, National Institute of Neurological Disorders and Stroke, NIH grant R01 AI071199.