Idiosyncratic adverse drug reactions present a challenge for drug development and clinical use, often caused by liver xenobiotic enzyme catalyzed bioactivation. The common prevention strategy of avoiding structural alerts in drug design is prone to false predictions. Deeper mechanistic knowledge of drug bioactivation mechanisms can inform safer drug design and patient use. Herein, I strategically integrated investigative methodologies to elucidate bioactivation and detoxification pathways for two marketed drugs. Deep-learning neural network models enabled high-throughput predictions of drug metabolism and analysis of patient data. Follow-up in vitro experiments using enzyme systems enabled targeted studies of drug metabolism kinetics and phenotyping. First, a study of the antifungal terbinafine identified a complex multi-pathway series of N-dealkylations catalyzed by seven different P450s leading to formation of a reactive aldehyde, reinforcing the difficulty in predicting terbinafine-induced liver injury. Second, a comparative study of thiazole epoxidation for sudoxicam and its safer marketed derivative meloxicam revealed that thiazole substituents can determine toxicity risks by impacting both bioactivation and detoxification. Contrasting enzyme contributions along the pathways implied a major role for enzyme specificity in determining outcomes. Overall, new mechanistic knowledge for specific drug bioactivation was achieved by leveraging the strengths of two different investigational approaches. These findings deepen our understanding of how structural alerts translate to risks of liver injury, and newly discovered targets for identifying toxicity predictive factors in patients offer exciting opportunities for future studies of clinical outcomes for these and similar drugs.
|Advisor:||Miller, Grover P.|
|Commitee:||Eoff, Robert, Swamidass, S. Joshua, Bhattacharyya, Sudeepa, Hendrickson, Howard|
|School:||University of Arkansas for Medical Sciences|
|Department:||Biochemistry and Molecular Biology|
|School Location:||United States -- Arkansas|
|Source:||DAI-B 82/7(E), Dissertation Abstracts International|
|Subjects:||Biochemistry, Molecular biology, Medicine|
|Keywords:||Bioactivation, Cytochrome P450, Hepatotoxicity, Meloxicam, Terbinafine|
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