Jeong lab:Projects

Clinical Pharmacology and Drug Metabolism

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Altered drug metabolism during pregnancy Medication use in pregnancy is prevalent due to pre-existing medical conditions or newly developing disorders. This unavoidable drug treatment requires accurate pharmacokinetic information because under- or over-exposure may result in detrimental clinical outcomes not only to the mother, but also to the fetus. Limited clinical evidence suggests that pharmacokinetic profiles of drugs are altered during pregnancy. Specifically, metabolic pathway-dependent changes have been reported for hepatic drug metabolism during pregnancy. Jeong lab is interested in identifying factors responsible for altered drug metabolism and elucidating the underlying molecular mechanisms (funded by NICHD R01). Kruppel-like Factor 9 (KLF9) promotes cytochrome P450 (CYP) 2D6 expression during pregnancy in CYP2D6-humanized mice. Mol Pharmacol. 2014;86(6):727-35 [1] Altered expression of small heterodimer partner governs cytochrome P450 (CYP) 2D6 induction during pregnancy in CYP2D6-humanized mice. J Biol Chem. 2014;289(6):3105-13 [2] Estradiol induces cytochrome P450 2B6 expression at high concentrations: Implication in estrogen-mediated gene regulation in pregnancy. Biochem Pharmacol. 2012;84(1):93-103 [3] Personalized medicine for CYP2D6 substrates CYP2D6 is a major drug-metabolizing enzyme, responsible for metabolizing ~20% of marketed drugs. CYP2D6-mediated drug metabolism exhibits very large inter-individual variability. While this can be explained in part by genetic polymorphisms of CYP2D6 gene, large portion of the variability remains unexplained. Jeong lab has been trying to better understand transcriptional regulation of CYP2D6. Based on accumulating data, we are in the process of identifying novel factors leading to CYP2D6 variability (in healthy human liver tissues) and elucidating the molecular mechanisms (funded by NIGMS R01). Estrogen-induced cholestasis leads to repressed CYP2D6 expression in CYP2D6-humanized mice. Mol Pharmacol. 2015;88(1):106-12 [4] Farnesoid X receptor agonist represses cytochrome P450 2D6 expression by upregulating small heterodimer partner. Drug Metab Dispos. 2015;43(7):1002-7 [5] Testing "druggability" of lead compounds Preclinical characterization of pharmacokinetics of a drug candidate is essential in drug development processes. Jeong lab provides our expertise in preclinical pharmacokinetics for development of antiviral and antibiotic agents (funded by NIAID R37, PI: Arun Ghosh at Purdue University). Metabolism-directed structure optimization of benzimidazole-based Francisella tularensis enoyl-reductase (FabI) inhibitors. Xenobiotica. 2014;44(5):404-16 [6] Warfarin pharmacogenomics Pharmacokinetic profiles of drugs are influenced by various factors such as genetic make-up of a person. For example, presence of certain genetic variants in drug metabolizing enzymes (e.g., CYP2C9*8) is associated with lower maintenance doses of warfarin in African Americans. We previously investigated the molecular mechanisms underlying the effects of genetic variations on pharmacokinetics of warfarin. CYP2C9 promoter region SNPs linked to the R150H polymorphism are functional suggesting their role in CYP2C9*8-mediated effects. Pharmacogenetics and Genomics. 2013;23(4):228-31. [7]