November 5, 2020

Mary “Allie” Schleiff student highlight

Allie is a GPIBS Ph.D. student in the Biochemistry and Molecular Biology track. She is a 4th year student in the laboratory of Dr. Grover Paul Miller.

She graduated from Henderson State University in 2017 with a Honors Bachelors of Science in Biochemistry and a minor in Biology, and she received a regulatory sciences certification from the UAMS Department of Environmental and Occupational Health in Spring 2020.

Research Interest Statement

My research focuses on a subset of structurally similar non-steroidal anti-inflammatory drugs (NSAIDs) known as diphenylamine NSAIDs. Diphenylamine NSAIDs are taken more than 15 million times each year in the United States, but roughly 15% of all people administered diphenylamine NSAIDs have a clinically observable case of hepatotoxicity from the compounds. Previous studies identified that diphenylamine hepatotoxicity is dependent upon metabolic bioactivation and varied depending upon minor structural modifications to the diphenylamine structural scaffold, but little work exists to identify the specific mechanisms by which diphenylamines cause hepatotoxicity. I used computational tools to identify potential diphenylamine metabolic bioactivations in seven marketed or withdrawn diphenylamine drugs and experimentally validate these computational results. Thus far, I have discovered that diphenylamine NSAIDs are preferentially bioactivated into quinone-species metabolites in variable amounts and by a variety of cytochrome P450 enzymes dependent upon minor structural modifications to the diphenylamine scaffold. I hope that results from this work can help direct future development of diphenylamine-containing drugs in the future and help identify and stratify patients at-risk following diphenylamine NSAID dosage to promote more personalized patient care.

Something Notable about Time as a Graduate Student

I am so grateful that I was trained as a fresh graduate student by Dr. Dusty Barnette. I was always dropping things, breaking things, and having the same information repeated to me over and over again and Dusty never batted an eye, scolded me, or made me feel like a burden. Specifically, I’m appreciative to him for always getting the tall things off the high shelves for me!

Career Goals

My dream job would be in a contract research organization conducting preclinical and clinical studies for pharmaceutical clients. Once I obtain my PhD, I intend to take a post-doctoral position through the Center for Drug Evaluation and Research (CDER) to enhance my regulatory experience and make myself more marketable!

Experiment or Technique You Would Most Like to Do

Nuclear magnetic resonance is a major technique used frequently in regulatory science and in the pharmaceutical industry, but my only exposure to it was for a week or so as an undergraduate in my Analytical Chemistry course. I was overwhelmed and scared of it then and I still am, though I want to change that!

Fun fact

Cleaning is legitimately one of my favorite hobbies, so most laboratories stress me out a bit – ha. If I wasn’t working in science, I would want to be a professional home organizer.

Publications

  1. Schleiff, M., Payakachat, S., Schleiff, B., Pinson, A., Flynn, N., Province, D., Boysen, G., Swamidass, S. J., Miller, G. P. “Significance of Multiple Bioactivation Pathways for Meclofenamate as Revealed through Modeling and Reaction Kinetics.”
    • Publication – Accepted, Drug Metabolism and Disposition.
  2. Barnette, D., Schleiff, M., Datta, A., Flynn, N., Swamidass, S. J., Miller, G. P. “Meloxicam Methyl Group Determines Enzyme Specificity for Thiazole Bioactivation Compared to Sudoxicam.”
    • Publication – Accepted, Toxicology Letters.
  3. Pinson, A., Pouncey, D., Schleiff, M., Fantegrossi, W., Prather, P., Radominska-Pandya, A., Boysen, G., Miller, G. P. “Significance of Competing Metabolic Pathways for Synthetic Cannabinoid 5F-APINACA as Revealed through Novel Reaction Kinetics.”
    • Publication – Published, Molecules. DOI: 3390/molecules25204820
  4. Schleiff, M., Russell, L., Gonzalez, E., Bart, A., Broccatelli, F., Humphreys, G., Scott, E., Segall, M., Prasad, B., Hartman, J., Lauschke, V., Nwabufo, C., Takahashi, R., Durmus, S., Nichols, C., Martin, I., and Taub, M., Sodhi, J. “Advances in the Study of Drug Metabolism – Symposium Report of the 12th Meeting of the International Society for the Study of Xenobiotics (ISSX).”
    • Publication – May 2020, Drug Metabolism Reviews. DOI: 1080/03602532.2020.1765793
  1. Barnette, D., Schleiff, M., Flynn, N., Payakachat, S., Osborn, L., Swamidass S., J., and Miller G. P. “Dual Mechanisms Suppress Meloxicam Bioactivation Relative to Sudoxicam.”
    • Publication – May 2020, Toxicology. DOI: 1016/j.tox.2020.152478
  2. Barnette, D., Davis, M., Flynn, N., Pidugu, A., Swamidass S. J., and Miller G. P. “Comprehensive Kinetic and Modeling Analyses Revealed CYP2C9 and 3A4 Determine Terbinafine Metabolic Clearance and Bioactivation.”
    • Publication – October 2019, Biochemical Pharmacology. DOI: 1016/j.bcp.2019.113661
  3. Davis, M., Barnette, D., Flynn, N., Pidigu, A., Swamidass, S. J., Boysen, G., Miller, G. P. “CYP2C19 and 3A4 Dominate Metabolic Clearance and Bioactivation of Terbinafine Based on Computational and Experimental Approaches.”
    • Publication – March 2019, Chemical Research in Toxicology. DOI: 1021/acs.chemrestox.9b00006
  4. Boysen, G., Davis, M., Siegel, E.R., Dings, R., Jamshidi-Parsian, A., Griffin, R. J. “Glutamine inhibitor CB-839 Increases Radiation Sensitivity of Lung Tumor Cells and Human Lung Tumor Xenografts in Mice.”
    • Publication – December 2018, International Journal of Radiation Biology. DOI: 1080/09553002.2018.1558299
  5. Barnette, D., Davis, M., Dang, N. L., Pidugu, A., Hughes, T., Swamidass, S. J., Boysen, G., Miller, G. P. “Lamisil (terbinafine) Toxicity: Determining Pathways to Bioactivation through Computational and Experimental Approaches.”
    • Publication – August 2018, Biochemical Pharmacology. DOI: 1016/j.bcp.2018.07.043
  6. Barber, M., Petrie, J., Wickham, R., Madsen, K., Davis, M., Smith, C. T., Hasan, M. “Environmental Impact Analysis to Support Biofuel Development in the Pacific Northwest.”
    • Publication (Progress Report) – September 2017. URI: 2376/12236

Grants

I am partially supported by a training grant through the Pharmacology, Toxicology, and Experimental Therapeutics Department in the UAMS Graduate School entitled, “Systems Pharmacology and Toxicology” (T32GM106999).

Awards

  • 2020 3rd Place Bhuvan Award for Excellence in Biochemistry Graduate Research – University of Arkansas for Medical Sciences Student Research Day
  • 2020 Top 30 Finalist with Honorarium – Sternfels Prize in Drug Safety Discoveries
  • 2020 Pfizer Society of Toxicology National Conference Student Travel Award – Society of Toxicology Computational Toxicology Specialty Section
  • 2019 First Place Oral Presentation – University of Arkansas for Medical Sciences Graduate Student Association Research Symposium
  • 2019 South Central Chapter Society of Toxicology Regional Conference Travel Award
  • Graduate Student Achievement Award for Selection to the Drug Metabolism Reviews Editorial Board – University of Arkansas for Medical Sciences Fall Research Award Ceremony
  • Graduate Student Achievement Award for Selection to the International Society for the Study of Xenobiotics New Investigator Group – University of Arkansas for Medical Sciences Fall Research Award Ceremony
  • 2019 Outstanding Graduate Student Poster Presentation – Drug Discovery and Development Colloquium
  • 2019 Invited Speaker with Honorarium – Drug Metabolism and Pharmacokinetics Symposium hosted by Genentech
  • 2018 MC-Bios Computational Biology Conference Travel Award – Midsouth Computational Biology and Bioinformatics Society