The long-term goal of this project is to better understand drug-drug interactions that arise primarily from the inhibitory effects of drug metabolites, rather than from the effects of the drugs themselves. It is well established that metabolites of drugs can be toxic, pharmacologically active, a cause of clinically significant drug-drug interactions and/or the source of non-linear drug pharmacokinetics. Thus, metabolites often play an important role in therapeutics. Metabolite-based drug interactions that arise from the inhibitory effects of drug metabolites, rather than the parent drugs, on P450 enzyme activity are poorly understood and difficult to predict. Rationalization of these types of interaction requires simultaneous resolution of two of the major scaling issues that plague drug metabolism research - (1) the application of in vitro data for a drug in order to predict in vivo metabolite pharmacokinetics and (2) prediction of the magnitude of a drug-drug interaction caused by a drug (in this case a metabolite) in vivo. The goal of this application is to establish theoreticallybased and experimentally verified means to understand, detect and more reliably predict metabolicallybased drug interactions.
Aim 1 completes our in vivo and in vitro work on the stereoselective metabolism of itraconazole (a potent inhibitor of drug metabolism in vivo) and the effects of the long lived, tight binding metabolites on enzyme activity and dose dependent pharmacokinetics of the parent drug.
Aim 2 focuses on a rationalization of the magnitude of drug-drug interactions that occur as the result of long term dosing of fluoxetine with drugs that are cleared by CYP2D6, CYP2C19 and CYP3A4 and the role of fluoxetine metabolites in these interactions. Experimental approaches use single recombinant enzymes, hepatocytes and in vivo interaction studies to test our predictions.
Aim 3 extends our work on the complexities of the irreversible inhibition of CYP3A4 by diltiazem and it's metabolites in single enzyme systems, microsomes and hepatocytes. The major objective here is to establish and rationalize new methods to meaningfully quantify in vitro behavior when the inhibition is almost entirely driven by the concentrations of diltiazem's metabolites. .Successful completion of these aims will provide powerful new tools to use in the prospective evaluation of metabolite-based drug interactions.
|Manoj, Kelath Murali; Parashar, Abhinav; Gade, Sudeep K et al. (2016) Functioning of Microsomal Cytochrome P450s: Murburn Concept Explains the Metabolism of Xenobiotics in Hepatocytes. Front Pharmacol 7:161|
|Shirasaka, Y; Chaudhry, A S; McDonald, M et al. (2016) Interindividual variability of CYP2C19-catalyzed drug metabolism due to differences in gene diplotypes and cytochrome P450 oxidoreductase content. Pharmacogenomics J 16:375-87|
|McDonald, Matthew G; Au, Nicholas T; Rettie, Allan E (2015) P450-Based Drug-Drug Interactions of Amiodarone and its Metabolites: Diversity of Inhibitory Mechanisms. Drug Metab Dispos 43:1661-9|
|Chaudhry, Amarjit S; Prasad, Bhagwat; Shirasaka, Yoshiyuki et al. (2015) The CYP2C19 Intron 2 Branch Point SNP is the Ancestral Polymorphism Contributing to the Poor Metabolizer Phenotype in Livers with CYP2C19*35 and CYP2C19*2 Alleles. Drug Metab Dispos 43:1226-35|
|Stamper, Brendan D; Garcia, Michael L; Nguyen, Duy Q et al. (2015) p53 Contributes to Differentiating Gene Expression Following Exposure to Acetaminophen and Its Less Hepatotoxic Regioisomer Both In Vitro and In Vivo. Gene Regul Syst Bio 9:1-14|
|Liu, Li; Collier, Ann C; Link, Jeanne M et al. (2015) Modulation of P-glycoprotein at the Human Blood-Brain Barrier by Quinidine or Rifampin Treatment: A Positron Emission Tomography Imaging Study. Drug Metab Dispos 43:1795-804|
|Ho, Han Kiat; Chan, James Chun Yip; Hardy, Klarissa D et al. (2015) Mechanism-based inactivation of CYP450 enzymes: a case study of lapatinib. Drug Metab Rev 47:21-8|
|Chapron, Brian; Risler, Linda; Phillips, Brian et al. (2015) Reversible, time-dependent inhibition of CYP3A-mediated metabolism of midazolam and tacrolimus by telaprevir in human liver microsomes. J Pharm Pharm Sci 18:101-11|
|Hsiao, Peng; Unadkat, Jashvant D (2014) Predicting the outer boundaries of P-glycoprotein (P-gp)-based drug interactions at the human blood-brain barrier based on rat studies. Mol Pharm 11:436-44|
|Sager, J E; Lutz, J D; Foti, R S et al. (2014) Fluoxetine- and norfluoxetine-mediated complex drug-drug interactions: in vitro to in vivo correlation of effects on CYP2D6, CYP2C19, and CYP3A4. Clin Pharmacol Ther 95:653-62|
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