The use of drug transporters as therapeutic targets.

Current Developments in Oncology Drug Research Section Editor: Mark J. Ratain, MD The Use of Drug Transporters as Therapeutic Targets Kathleen M. Giacomini, PhD Professor and Co-Director UCSF-Stanford Center of Excellence in Regulatory Sciences and Innovation UCSF School of Pharmacy San Francisco, California H&O What is the role of transporters in cell biology? KG Transporters are proteins that play a role in bring- ing small molecules—such as endogenous compounds, vitamins, amino acids, nutrients, and drugs—across biological membranes. Transporters may mediate influx or efflux, or they may be bidirectional. Bidirectional transporters facilitate the movement of substrates across membranes in either direction from the intracellular to the extracellular compartments or vice versa. Transporters that are predominantly influx bring substrates into the cell. Transporters acting as efflux pumps protect organs by pumping drugs and other substances out of the cell. My research focuses mostly on transporters on the plasma membrane or the cell membrane. It encompasses 3 major areas: transporters in absorption, distribution, metabolism, and elimination (known as ADME), the pharmacogenomics of transporters, and the endogenous role of transporters that have been predominantly char- acterized as drug transporters. I work on the solute car- rier superfamily, which contains almost 400 transporters throughout the human genome. They are clustered into 52 families. Each transporter is unique and does some- thing different. H&O What is the goal of your research? KG Within the areas of pharmacogenomics and ADME, the goal is to determine how transporters may affect varia- tion in drug response and drug levels. For example, there may be genetic variants in transporters that people carry that cause them to respond differently to a given drug. Another goal is to determine the endogenous role of those transporters that have been predominantly characterized as drug transporters. Many transporters play a significant role in normal human physiology as well as in disease. I would like to know what these transporters do when they are not interacting with drugs. H&O In what ways do transporters act on drugs? KG Drug transporters can act in several ways, which are specific to each organ. In the intestines, some transport- ers bring drugs into the body and enhance their absorp- tion. Other transporters in the intestine protect the body against ingested toxins from plants and animals. These transporters modulate drug absorption by pumping the drugs out of the intestine or keeping them in the intes- tinal lumen. Transporters can bring drugs into the liver where they can be metabolized. In the kidneys, transport- ers can actively eliminate drugs so that they are excreted in the urine. Sometimes transporters may serve to facilitate reabsorption of drugs in the kidneys. Within the blood- brain barrier, transporters can bring drugs into the brain or keep them out. H&O How are transporters used as therapeutic targets? KG The use of transporters as therapeutic targets is an interesting new field of study. In 2015, my colleagues and Clinical Advances in Hematology & Oncology Volume 14, Issue 11 November 2016 869 Drug Development ADVANCES IN DRUG DEVELOP MENT