Erin G. Schuetz Lab

Our study of pharmacogenetics allows us to understand the influence of genes on drug metabolism and transport. We are particularly interested in genes that encode proteins that influence drug metabolism, transport, and the regulation of these processes.  Our research focuses on the CYP drug metabolism enzymes, particularly the CYP3A family, that helps metabolize half of all clinically administered drugs. In our work, we partner with investigators at other institutions to determine the association of newly identified CYP3A4 and 3A5 genetic variants to disposition of CYP3A substrates in order to better predict the right dose for each patient.

A major effort within our laboratory is the creation of advanced preclinical models to examine metabolism and transport processes and how they may impact a drug’s efficacy. In our development of preclinical models, our goal is to study the influence of drug transporters on drug disposition and predict their role in drug-drug interactions (DDI). Our laboratory develops models to study a variety of environments that may impact drug disposition.

• In vivo/in vitro assay to monitor BCRP-mediated DDIs
  BCRP is an important drug efflux transporter prone to potential DDIs. Given the promiscuity of these transporters, they can efflux a variety of drugs and recognize a multitude of substrates, which increases the potential for DDIs. Discerning potential DDIs early in the pharmaceutical development process is imperative to ensure safety and efficacy. To aid in this effort, our laboratory studies the DDI potential at the intestine, liver and kidney using a florescent substrate for BCRP. The use of this florescent substrate allows us to characterize the DDI potential of novel BCRP-inhibitor drugs.
  
  
• Study of PGP substrate penetration to improve treatment of CNS tumors
  Expression of the efflux transporter P-glycoprotein (PGP) at the blood-brain barrier and blood-cerebrospinal fluid (CSF) barrier (including the arachnoid barrier and choroid plexus) prevents blood-to-brain and blood-to-CSF drug movement. Currently, there are not many reliable preclinical models available for the study of CSF/brain tumor treatments. To remedy this, our laboratory built a transgenic preclinical model that models PGP at the choroid plexus. The development, and continued improvement, of this model will allow us to predict the influence of PGP on drug disposition in the treatment of CNS tumors.
  
  
• MRP4 knockout models
  In these knockout experimental models, we can study how the presence or absence of the drug efflux transporter Mrp4 influences the disposition of both endogenous as well as drug substrates. Our work in these models is important as the models simulate what happens when a patient lacks this transporter or it becomes inhibited. Establishing this understanding will help us as we explore the pharmacokinetics of drug substrates as well as identify perturbations in endogenous substrates.

In the examination of small molecules and how they interact with their larger environment, our laboratory seeks to identify endogenous substrates of drug efflux transporters. Our studies use models that lack the drug efflux transporters BCRP, PGP, and MRP4. We conduct metabolomic analysis of fluids (CSF, urine, and plasma) to identify putative substrates so we can better understand the transporter’s overall endogenous functions, identify transporter biomarkers, and predict drug-induced metabolic alterations. Our work in this area will help elucidate how changes in metabolic pools due to transporter inhibition could cause metabolic changes and rewire drug sensitivity indirectly.