Drug Transporters

Pharmacokinetics describes how the body handles drugs. Each of the processes in pharmacokinetics (absorption, distribution, metabolism, and excretion) can be influenced by membrane proteins called transporters.  Transporters can either help drugs get across biological barriers (such as the gut lining) or work to exclude them from a part of the body (such as the brain).  Transporters are direct targets for many drugs, and most drugs are thought to interact with at least one transporter. Additionally, transporters can work together with drug metabolizing enzymes to eliminate drugs from the body.  Research on drug transporters involves many disciplines of science and offers many possibilities for scientific investigations.

Organic Solute Carriers (SLC22 transporter family)

Organisms encounter a diverse array of potentially hazardous substances on a daily basis, including medications, plant and animal toxins, and products of cellular metabolism. An individual’s ability to survive these exposures greatly depends upon the efficiency of the excretory and detoxifying organs of the body. Dr Sweet’s research focus is on the organic cation/anion/zwitterion transporter (SLC22) family that is responsible for the transport of organic solutes in liver, kidney, choroid plexus, and brain capillary endothelium. Understanding the mechanisms these transporters utilize to protect the body and brain from fluctuations in the composition of the blood and cerebrospinal fluid has provided unique insight into toxicity, drug-drug interaction, and human disease states.

Dr. Sweet’s research group uses cell culture, intact tissue, and knockout mouse model systems to: (1) determine the energetics and specificity of the transporters, (2) define the roles of transporters in drug interactions and disease, and (3) identify the mechanisms involved in the modulation of transporter function and expression.

Examination of cloned SLC22 transporters expressed in isolation has yielded a wealth of information about individual organic cation transporter (OCT) and organic anion transporter (OAT) substrate selectivity, affinity, and driving forces. Evidence indicates they are intimately involved in the distribution and elimination of many potentially toxic endogenous and exogenous organic cations and anions. Indeed, the nature of these substrates suggests that proper OCT and OAT function is essential to maintaining total body homeostasis and that altered OCT/OAT function (and/or expression) may be a key factor in the progression of certain disease states and may provide a molecular basis for understanding the varied responses of infants, children, and adults to the same medication or toxic insult.

Dr. Sweet’s Faculty Page

Placental Drug Transport

Health care practitioners have inadequate data regarding drug use in pregnant women.  Additionally, the pharmaceutical industry is not required or motivated to perform more than minimal testing to determine if and how their drugs can be used safely in pregnancy.  Furthermore, many women need medications during pregnancy, and despite a lack of information the use of medications and dietary supplements in pregnancy is increasing.  Large clinical trials to determine the safety and efficacy of numerous medications or dietary supplements would be impractical.  However, a better understanding of the mechanisms regulating fetal exposure would provide health care practitioners more scientific evidence upon which to base drug therapy decisions.

To address this clinical problem, Dr. Gerk is investigating human placental drug transport mechanisms. Specifically, Dr. Gerk's research is focused on ATP-Binding Cassette (ABC) transporters in the human placenta. These are proteins positioned at the maternal-fetal interface which may control the extent to which drugs cross the placenta.  The expression and function of these transporters may be altered by certain diseases, concurrent medications, dietary components, as well as genetic or environmental factors. Dr. Gerk’s lab uses a multidisciplinary, collaborative approach to investigate these issues, and includes aspects of clinical research, cell/tissue culture, biopharmaceutics, pharmacokinetics, transporter biochemistry, and molecular biology.  This lab interacts with the PK/PD research group as well as faculty in the departments of Obstetrics & Gynecology, Pharmacology & Toxicology, and Medicinal Chemistry.

Current projects in Dr. Gerk’s lab include investigations on the influence of pregnancy conditions such as preeclampsia and gestational diabetes on ABC transporter expression and function, as well as strategies to improve the transplacental delivery of antiretroviral medications.  Research opportunities may exist depending on the availability of funding.