By Patrick T. Ronaldson
Drug transporter research is growing at an unprecedented pace. Considerable progress has been made in this exciting field, particularly with respect to clinical translation of preclinical data, understanding the role of transporter polymorphisms on interindividual differences in drug response, and regulation of drug transporters by disease states and by drugs themselves.
Transporters also have an incredible potential to be targeted for control of drug tissue disposition. For example, pharmacological treatment of central nervous system (CNS) diseases (i.e., stroke, traumatic brain injury, neurodegenerative diseases, cancer) requires that drugs achieve efficacious brain concentrations. Considerable research has focused on studying mechanisms that limit CNS drug penetration at the blood-brain barrier (BBB) by describing the role of ATP-binding cassette (ABC) transporters (i.e., P-glycoprotein (P-gp), multidrug resistance proteins (MRPs), and breast cancer resistance protein (BCRP)). Clinical trials targeting P-gp with small molecule inhibitors have been unsuccessful in improving CNS drug delivery due to inhibitor toxicity and/or enhanced tissue penetration. Clearly, molecular targeting of efflux transporters with the objective of enhancing brain drug uptake is not therapeutically effective. In particular, it is counterintuitive to target proteins that transport drugs out of a tissue for the purpose of getting a drug into a tissue.
Perhaps a more viable alternative is to target uptake transporters such as members of the solute carrier (SLC) superfamily. With respect to the brain, this strategy enables delivery of neuroprotective drugs for treatment of diseases such as stroke. For example, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (i.e., statins) have been shown to exert neuroprotective effects in preclinical studies and are also well-known substrates for organic anion transporting polypeptides (OATPs), members of the SLC superfamily. Clinical studies have shown that statins are also associated with early neurological improvement following stroke. Understanding the role of OATP isoforms on the CNS delivery of drugs such as statins will provide vital information that will facilitate development of more effective neuroprotective drugs.
Targeting transporters is not limited to brain barrier sites. Targeting transporters at nontraditional barriers (i.e., cornea, epidermis, lung) as well as in the gastrointestinal tract, liver, and kidney also offer a unique potential to provide improved pharmacotherapy via development of medicines that are both safer and more efficacious. In order for research in transporter targeting to produce state-of-the-art scientific breakthroughs, it is essential that consistent knowledge exchange occur between academic, industrial, and regulatory scientists. Such collaborative partnerships will enable preclinical data to move from the bench to the bedside and facilitate the ultimate goal of pharmacological research: better drugs and more effective therapies for a multiplicity of diseases.
The 2015 AAPS Annual Meeting and Exposition program highlights the role of transporters in drug development. Such transporter-based programming includes the short course Transporter Boot Camp: Back to Basics and Strategies for Launching Transporter Studies, which highlights cutting-edge methodologies for studying transporters. The program also includes state-of-the-art programming on the impact of transporters on drug development and regulatory decision-making. These scientific sessions are essential learning opportunities for those pharmaceutical scientists with particular interests in this exciting and cutting-edge field.