Drug-metabolizing enzymes (DMEs) play an essential role in determining the pharmacokinetics (PK) of medications and the ensuing therapeutic outcomes. The interindividual variability in the expression and activity of DMEs is a major contributing factor to the variation in PK and drug response and can lead to treatment failure and unexpected adverse reactions. Thus, identifying biomarkers capable of predicting the function of DMEs and using the biomarkers to tailor drug treatment can improve the efficacy and safety of pharmacotherapy. Previous pharmacogenomics studies identified many genetic variants of DMEs associated with the PK and pharmacodynamics (PD) of therapeutic agents, and pharmacogenomics of DMEs have been increasingly utilized in the clinic to guide precision pharmacotherapy. However, the improvement achieved by the implementation of DME pharmacogenomics is somewhat limited in part due to that a significant portion of DME variability cannot be accounted for by the identified genetic variants. Thus, there is a critical need to identify biomarkers that can reliably predict in vivo DME functions.
The major DMEs include cytochrome P450s (CYPs), UDP-glucuronoslytransferases (UGTs), and esterases. The expression patterns of DMEs vary significantly among different enzymes. In general, the liver, intestine, and kidney exhibit the most abundant DME levels and are considered the primary organs responsible for drug metabolism. Plasma DMEs are believed to be released from organs with high DME expression levels, such as the liver. It has been well established that major DMEs including CYPs and UGTs are present at a very low level in human plasma and these plasma DMEs do not significantly contribute to the metabolism of their substrates. Our preliminary study suggests that plasma DME proteins may reflect their expression levels in the tissues (e.g., the liver) involved in drug metabolism and thus could serve as biomarkers for the prediction of the PK and PD of drugs metabolized by the enzymes.
In this project, we will conduct a healthy volunteer PK study using a five-probe metabolic cocktail for CYP1A2, 2C9, 2C19, 2D6, and 3A4/5 (i.e., caffeine: CYP1A2; losartan: CYP2C9; omeprazole: CYP2C19; dextromethorphan: CYP2D6; and midazolam: CYP3A4/5) to determine whether plasma CYP proteins can serve as biomarkers to predict the PK of their substrate medications. Of note, the DMEs targeted in the study are involved in the metabolism of over 60% medications currently in clinical use. The project has the potential to revolutionize precision pharmacotherapy by developing a plasma DME proteomics-based approach to tailor treatment to individual patients, leading to the improvement of efficacy and safety of pharmacotherapy.
Please Note This Project Is Now Closed.
The Michigan Institute for Clinical & Health Research (MICHR) seeks innovative translational research projects that will ultimately have significant potential to improve patient and community health outcomes. The goal of this funding is to support interdisciplinary research teams in generating sufficient preliminary data to pursue future extramural funding and publication opportunities. We welcome research proposed at any stage of translation, including:
- preclinical research that aims to connect the basic science of disease with human medicine
- clinical research to better understand a disease in humans
- clinical implementation, involving the adoption of interventions demonstrated useful in the research environment into routine clinical care, and
- the study of health outcomes at the population level to determine the effects of diseases and efforts to prevent, diagnose and treat them
MICHR will fund up to five Classic Cubes ($60K) and 13 Mini Cubes ($15K).
No unit or faculty contribution is required.
Project Submission Process
Interested faculty members please provide the following information to be considered for funding:
Click the Comments tab above, and post a project idea in the Mcubed website. Please do not exceed two paragraphs in length. Provide basic details about the proposed research.
Comment should also include:
- Three cube collaborators - faculty names and units. The team must include 3 faculty from at least 2 units, and 1 faculty member on each team must be from Medicine.
- Grant amount requested ($15K or $60K)
- Studies proposing cell or animal models should provide reasoning of how the research will lead to immediate next step studies in humans.
Comments will be accepted until May 15, 2019.
Note: Project duration is one year from the transfer of funds.
For additional questions about this funding opportunity, please contact Beth LaPensee at email@example.com.
For eligibility requirements, use of funds, and details on the application process, please see: