Mary "Allie" Schleiff is the Drug Metabolism and Disposition Highlighted Trainee Author for the February 2021 issue. Ms. Schleiff is a pre-doctoral trainee in the Department of Biochemistry and Molecular Biology at the University of Arkansas for Medical Sciences. She conducts her research under the tutelage of Dr. Grover Paul Miller. The Drug Metabolism and Disposition article that earned her selection as a Highlighted Trainee Author is titled “Significance of Multiple Bioactivation Pathways for Meclofenamate as Revealed through Modeling and Reaction Kinetics” and is available at https://doi.org/10.1124/dmd.120.000254.
In her dissertation work, Ms. Schleiff applies bioinformatics, computational modeling, and experimental analysis to assess the impacts of minor structural modifications (halogenation, methylation, etc.) to diphenylamine NSAIDs on metabolic bioactivation and downstream hepatotoxicity. The diphenylamine structure has been shown to induce hepatotoxicity via metabolism-driven mitochondrial ATP depletion and changes to the mitochondrial permeability transition. Several in-development drugs utilize this diphenylamine structure. Within this manuscript, she identified the diphenylamine meclofenamate as an important molecule for computational and experimental proof-of-concept demonstrations and conducted assessments to identify potential metabolic bioactivation products. Four separate metabolic bioactivation pathways were identified and comprised over ten percent of total meclofenamate metabolism, thus highlighting a major and likely hepatotoxic endpoint for meclofenamate dosage.
Conclusions from Ms. Schleiff's work can be utilized for two applications. First, identifying "good" and "bad" structural modifications on the diphenylamine scaffold will provide insights on future diphenylamine drug development. Second, identification of bioactivating and detoxifying metabolizing enzymes of diphenylamine NSAIDs will help stratify patient populations who take these drugs into risk categories, thus promoting more personalized patient care.
When not in the lab, Allie enjoys playing video games and reading high fantasy novels. She also enjoys indulging herself in the lively Little Rock, Arkansas, craft beer scene.