Research & Projects
Research in the Giacomini laboratory is focused on a variety of projects associated with membrane transporters ranging from pharmacogenomics to its mechanisms.
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- Pharmacogenomics research projects
- Regulatory sciences projects
- Endogenous role of organic cation transporters
- Transporters mechanisms
Pharmacogenomics studies of metformin-induced glycemic response
Type 2 Diabetes (T2D) is a metabolic disease characterized by higher than normal fasting or post-meal glucose levels. In the US, about 29.1 million Americans are diagnosed with T2D. Metformin is the initial pharmacologic treatment of newly diagnosed T2D patients in the US. Despite its status as first line treatment in T2D, metformin monotherapy does not result in acceptable control of blood glucose levels in over 33% of patients. Furthermore, there is significant variation in the initial response to metformin.
Our laboratory published a large metformin response GWAS with replication (N = 10,298 from several cohorts) with the focus on the genetic determinants of initial glycemic response to metformin. The GWAS, conducted initially in patients of European ancestry, identified a genome-wide level significant association between rs8192675 in the SLC2A2 gene (encodes for a glucose transporter, GLUT2) and greater response to metformin (p = 2 x10-8). Also, rs8192675 significantly associated with increased metformin response in African-Americans, Latinos, East Asians groups. Our laboratory is interested in understanding the role of GLUT2 in response to metformin treatment and to identifying other genetic variants that underlie response to this highly used anti-diabetic drug.
Pharmacogenomics studies of allopurinol-induced hypouricemia response
Allopurinol is the first line treatment for chronic gout, a debilitating inflammatory disease characterized by high serum uric acid levels. Response to therapy is highly variable, and even in prospective trials with good adherence to allopurinol, few patients are able to maintain healthy uric acid levels over the long-term, putting them at an increased risk for developing chronic kidney disease and cardiovascular disease. Our laboratory was the first to identify genetic variants in the transporter gene, ABCG2, as determinants of allopurinol response (PMID:25676789). In support of our genetic findings, we determined that allopurinol and its active metabolite, oxypurinol, are substrates of Breast Cancer Resistance Protein (BCRP) an efflux transporter encoded by ABCG2. Since our initial analysis, we have been working closely with collaborators at Kaiser Permanente’s Research Program on Genes, Environment and Health (RPGEH) as well as the Pharmacogenomics Research Network (PGRN) to explore other potential genetic influences on allopurinol response using retrospective EHR data and genome-wide association studies. Our lab is also interested in characterizing the mechanisms by which these variants might mediate allopurinol’s pharmacologic action. Using in vitro models and prospective clinical trials, we aim to describe the role of ABCG2 and other genes in allopurinol pharmacokinetics and pharmacodynamics.
Research in regulatory science conducted in the Giacomini Lab is focused on collaborative research projects with scientists at the United States Food and Drug Administration (FDA) and particularly related to the role of membrane transporters in drug disposition, response, toxicity and in drug-drug interactions. Specific projects:
Drug transporters are present in various tissues and have a significant role in drug absorption, distribution, and elimination. As a result, transporter-mediated drug-drug interactions (DDIs) can lead to major cause of drug toxicities. The International Transporter Consortium, co-led by Kathy Giacomini, has identified 7 transporters which are responsible for clinically significant transporter-mediated drug-drug interactions. These transporters are: P-glycoprotein, breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic cation transporter (OCT) 2, organic anion transporters (OAT) 1, and OAT3. A major research project in our laboratory is to identify endogenous metabolites that could serve as qualified biomarkers for these aforementioned transporters and help predict potential drug-drug interactions. We used publicly available genomewide association studies and human metabolomics data to identify potential endogenous metabolites that are associated with genetic polymorphisms in these transporters. To date, we have identified several novel endogenous biomarkers for OATP. On-going studies are to discover other biomarkers for transporters and to determine whether some of them may be qualified for use in early phase of clinical studies in humans.
Drug-excipient interaction studies
Excipients are ubiquitously used in drug products to ensure drug stability, solubility, permeability, palatability and delivery. They are assumed, but rarely tested, to be inactive. The goal of current project is to explicitly characterize the interactions of FDA-approved oral excipients with intestinal transporters to determine if any excipient may affect transporter-mediated drug absorption in the intestine. This study will provide informative insights on the following aspects: (1) The effect of excipients on drug absorption, especially BCS class 3 drugs, of which permeability mainly relies on intestinal absorptive transporters; (2) Bioequivalence of generic drug products to brand name drugs, in which the excipients, in many cases, are not the same. Overall, this study will provide often under-appreciated and yet essential knowledge for FDA regulatory decision-making on rational use of excipients in drug products to ensure optimal therapeutic outcome in patients.
Drug-uremic toxin interaction studies
Accumulation of uremic solutes in the plasma is one of the characteristics of chronic kidney disease (CKD). Importantly, drug disposition and response could be altered in patients with CKD and could lead to higher drug levels and thus cause toxicities. Increased levels of endogenous uremic solutes can lead to CKD and thus affect renal function. Some of these uremic solutes are substrates of organic anion transporter (OAT) 1 and OAT3, which are major transporters in the basolateral membrane of the kidney proximal tubule cells and have been identified as the targets of potential DDIs. Using medium-throughput screening assays, we identified 12 and 13 solutes among the 72 uremic solutes as inhibitors of OAT1 and OAT3 respectively (see PMID: 27467266). On-going studies and future studies are needed to identify whether these uremic solutes inhibit OAT1 and OAT3 in vivo and whether these solutes also inhibit other drug transporters which can contribute to the decline in renal drug clearance in patients with CKD. This information will be used to guide FDA in making recommendations for studies in patients with CKD.
Medical countermeasures in special populations
In response to terrorist attacks that involve biological, chemical and nuclear threats, or emerging infectious diseases and natural disasters, medical countermeasures (MCMs), which include a list of FDA-approved therapeutics and devices, will be used to diagnose and treat the affected populations. Challenges exist when developing and ensuring the safety and effectiveness of MCMs for special populations, such as children, elderly and patients with impaired renal functions, due to physiological differences and limited data to reliably predict the pharmacokinetics. In our laboratory, ongoing studies are being done to characterize the differences in the expression levels and activities of renal transporters such as organic anion transporter (OAT) 1 and OAT3 in these special populations. Results from these studies will provide invaluable information to better predict drug absorption and disposition as the FDA develops safe and effective MCMs that may be used in these populations in case of public health emergencies.
Transporters as “gatekeepers” are expressed on the plasma membrane of various tissues, and play critical roles in movements of solutes such as metabolites, nutrients, bile salts, neurotransmitters, hormones and signaling molecules, and toxins to across cell membranes. In addition, many drugs are highly dependent on transporters in the paths of absorption, distribution, metabolism, and elimination (ADME). Though many drug transporters are well-characterized for their roles in drug absorption, elimination, toxicity and as determinants of drug action, the endogenous roles of most drug transporters are poorly understood. Our laboratory has a strong interest in understanding the physiologic roles of two transporters primarily characterized as drug transporters: organic cation transporter 1 (OCT1) and organic cation transporter 3 (OCT3).
In human and rodents, OCT1 is highly expressed in the liver. Previously, through metabolomic studies in cells overexpressing human OCT1 and Oct1-/- mice, our laboratory identified thiamine, vitamin B1, as the major endogenous substrate for organic cation transporter 1 (OCT1). On-going and further studies have demonstrated that mice with genetic deletions in Oct1 have reduced hepatic steatosis and other phenotypes likely linked to altered hepatic thiamine disposition. Further these mice are more resistant to the pathological consequences associated with thiamine deficient diets than wildtype mice. These results have strong implications to humans with reduced function polymorphisms of OCT1. OCT3 is expressed ubiquitously in most tissues such as lung, adipose tissue, liver, small intestine, kidney, and muscle. OCT3 plays a role in transporting many monoamine neurotransmitters, hormones, and steroids. Genome-wide association study (GWAS) shows that it is associated with cancer and lipid dysfunction. Using the Oct3-/- mouse model, our laboratory is interested in determining the mechanisms responsible for its associations with various cancers and lipid disorders.
Another important project in the Giacomini Lab is to characterize the mechanisms of membrane transporters that are drug targets. In human, there are 386 SLC transporters, many of which contribute to the absorption, distribution, metabolism, and excretion of drugs and/or can be targeted directly by therapeutics. Over the last several years, the atomic structures of SLC transporters determined by X-ray crystallography and NMR spectroscopy have significantly expanded the applicability of structure-based prediction of SLC transporter ligands, by enabling both comparative modeling of additional SLC transporters and virtual screening of small molecules libraries against experimental structures as well as comparative models. Our laboratory collaborates with Andrej Sali, PhD, and Avner Schlessinger, PhD, to develop and apply computational tools to annotate the function of membrane transporters. High-throughput screening of small molecules also provide structure activity information on ligand transporter interactions. Several transporter studies have been published through this collaboration: LAT1, NET, GAT2, OCT3 and MATE2.