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Research ArticleSymposium Report

Interindividual Variability in Cytochrome P450–Mediated Drug Metabolism

Timothy S. Tracy, Amarjit S. Chaudhry, Bhagwat Prasad, Kenneth E. Thummel, Erin G. Schuetz, Xiao-bo Zhong, Yun-Chen Tien, Hyunyoung Jeong, Xian Pan, Laura M. Shireman, Jessica Tay-Sontheimer and Yvonne S. Lin
Drug Metabolism and Disposition March 2016, 44 (3) 343-351; DOI: https://doi.org/10.1124/dmd.115.067900
Timothy S. Tracy
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky (T.S.T.); Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (A.S.C., E.G.S.); Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (B.P., K.E.T., L.M.S., J.T.-S., Y.S.L.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut (X.Z., Y.-C.T); and Departments of Pharmacy Practice and Biopharmaceutical Sciences, College of Pharmacy, University of Illinois, Chicago, Illinois (H.J., X.P.)
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Amarjit S. Chaudhry
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky (T.S.T.); Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (A.S.C., E.G.S.); Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (B.P., K.E.T., L.M.S., J.T.-S., Y.S.L.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut (X.Z., Y.-C.T); and Departments of Pharmacy Practice and Biopharmaceutical Sciences, College of Pharmacy, University of Illinois, Chicago, Illinois (H.J., X.P.)
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Bhagwat Prasad
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky (T.S.T.); Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (A.S.C., E.G.S.); Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (B.P., K.E.T., L.M.S., J.T.-S., Y.S.L.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut (X.Z., Y.-C.T); and Departments of Pharmacy Practice and Biopharmaceutical Sciences, College of Pharmacy, University of Illinois, Chicago, Illinois (H.J., X.P.)
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Kenneth E. Thummel
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky (T.S.T.); Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (A.S.C., E.G.S.); Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (B.P., K.E.T., L.M.S., J.T.-S., Y.S.L.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut (X.Z., Y.-C.T); and Departments of Pharmacy Practice and Biopharmaceutical Sciences, College of Pharmacy, University of Illinois, Chicago, Illinois (H.J., X.P.)
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Erin G. Schuetz
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky (T.S.T.); Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (A.S.C., E.G.S.); Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (B.P., K.E.T., L.M.S., J.T.-S., Y.S.L.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut (X.Z., Y.-C.T); and Departments of Pharmacy Practice and Biopharmaceutical Sciences, College of Pharmacy, University of Illinois, Chicago, Illinois (H.J., X.P.)
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Xiao-bo Zhong
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky (T.S.T.); Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (A.S.C., E.G.S.); Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (B.P., K.E.T., L.M.S., J.T.-S., Y.S.L.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut (X.Z., Y.-C.T); and Departments of Pharmacy Practice and Biopharmaceutical Sciences, College of Pharmacy, University of Illinois, Chicago, Illinois (H.J., X.P.)
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Yun-Chen Tien
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky (T.S.T.); Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (A.S.C., E.G.S.); Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (B.P., K.E.T., L.M.S., J.T.-S., Y.S.L.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut (X.Z., Y.-C.T); and Departments of Pharmacy Practice and Biopharmaceutical Sciences, College of Pharmacy, University of Illinois, Chicago, Illinois (H.J., X.P.)
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Hyunyoung Jeong
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky (T.S.T.); Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (A.S.C., E.G.S.); Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (B.P., K.E.T., L.M.S., J.T.-S., Y.S.L.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut (X.Z., Y.-C.T); and Departments of Pharmacy Practice and Biopharmaceutical Sciences, College of Pharmacy, University of Illinois, Chicago, Illinois (H.J., X.P.)
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Xian Pan
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky (T.S.T.); Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (A.S.C., E.G.S.); Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (B.P., K.E.T., L.M.S., J.T.-S., Y.S.L.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut (X.Z., Y.-C.T); and Departments of Pharmacy Practice and Biopharmaceutical Sciences, College of Pharmacy, University of Illinois, Chicago, Illinois (H.J., X.P.)
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Laura M. Shireman
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky (T.S.T.); Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (A.S.C., E.G.S.); Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (B.P., K.E.T., L.M.S., J.T.-S., Y.S.L.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut (X.Z., Y.-C.T); and Departments of Pharmacy Practice and Biopharmaceutical Sciences, College of Pharmacy, University of Illinois, Chicago, Illinois (H.J., X.P.)
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Jessica Tay-Sontheimer
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky (T.S.T.); Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (A.S.C., E.G.S.); Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (B.P., K.E.T., L.M.S., J.T.-S., Y.S.L.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut (X.Z., Y.-C.T); and Departments of Pharmacy Practice and Biopharmaceutical Sciences, College of Pharmacy, University of Illinois, Chicago, Illinois (H.J., X.P.)
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Yvonne S. Lin
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky (T.S.T.); Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (A.S.C., E.G.S.); Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (B.P., K.E.T., L.M.S., J.T.-S., Y.S.L.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut (X.Z., Y.-C.T); and Departments of Pharmacy Practice and Biopharmaceutical Sciences, College of Pharmacy, University of Illinois, Chicago, Illinois (H.J., X.P.)
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Abstract

The cytochrome P450 (P450) enzymes are the predominant enzyme system involved in human drug metabolism. Alterations in the expression and/or activity of these enzymes result in changes in pharmacokinetics (and consequently the pharmacodynamics) of drugs that are metabolized by this set of enzymes. Apart from changes in activity as a result of drug–drug interactions (by P450 induction or inhibition), the P450 enzymes can exhibit substantial interindividual variation in basal expression and/or activity, leading to differences in the rates of drug elimination and response. This interindividual variation can result from a myriad of factors, including genetic variation in the promoter or coding regions, variation in transcriptional regulators, alterations in microRNA that affect P450 expression, and ontogenic changes due to exposure to xenobiotics during the developmental and early postnatal periods. Other than administering a probe drug or cocktail of drugs to obtain the phenotype or conducting a genetic analysis to determine genotype, methods to determine interindividual variation are limited. Phenotyping via a probe drug requires exposure to a xenobiotic, and genotyping is not always well correlated with phenotype, making both methodologies less than ideal. This article describes recent work evaluating the effect of some of these factors on interindividual variation in human P450-mediated metabolism and the potential utility of endogenous probe compounds to assess rates of drug metabolism among individuals.

Footnotes

    • Received October 16, 2015.
    • Accepted December 16, 2015.
  • All authors contributed equally to this work.

  • This research was supported by the National Institutes of Health Eunice Kennedy Shriver National Institute of Child Health and Human Development [Grants R01HD065532 and R01HD058556]; the National Institutes of Health National Institute of General Medical Sciences [Grants T32GM007750, R01GM112746, and R01GM087376]; the National Institutes of Health National Institute of Environmental Health Sciences [Grants P30ES007033 and R01ES019487]; and the National Institutes of Health National Center for Advancing Translational Sciences [Clinical and Translational Science Awards TR000423, TR000421, and TR000001].

  • dx.doi.org/10.1124/dmd.115.067900.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 44 (3)
Drug Metabolism and Disposition
Vol. 44, Issue 3
1 Mar 2016
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Research ArticleSymposium Report

Interindividual Variability in P450s

Timothy S. Tracy, Amarjit S. Chaudhry, Bhagwat Prasad, Kenneth E. Thummel, Erin G. Schuetz, Xiao-bo Zhong, Yun-Chen Tien, Hyunyoung Jeong, Xian Pan, Laura M. Shireman, Jessica Tay-Sontheimer and Yvonne S. Lin
Drug Metabolism and Disposition March 1, 2016, 44 (3) 343-351; DOI: https://doi.org/10.1124/dmd.115.067900

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Research ArticleSymposium Report

Interindividual Variability in P450s

Timothy S. Tracy, Amarjit S. Chaudhry, Bhagwat Prasad, Kenneth E. Thummel, Erin G. Schuetz, Xiao-bo Zhong, Yun-Chen Tien, Hyunyoung Jeong, Xian Pan, Laura M. Shireman, Jessica Tay-Sontheimer and Yvonne S. Lin
Drug Metabolism and Disposition March 1, 2016, 44 (3) 343-351; DOI: https://doi.org/10.1124/dmd.115.067900
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  • Article
    • Abstract
    • Introduction
    • Genetic Predictors of P450 Expression and Activity (E.G.S., B.P., K.E.T., and A.S.C.)
    • Effects of Drug Treatment at Early Life on Interindividual Variations of P450-Mediated Drug Metabolism in Adult Liver (X.Z. and Y.-C.T.)
    • Interindividual Variability in CYP2D6-Mediated Drug Metabolism (H.J. and X.P.)
    • Biomarkers of P450 Activity Using Metabolomic Approaches (L.M.S., J.T.-S., and Y.S.L.)
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  • Physiological Regulation of Drug Transport and Metabolism
  • P450 System Protein-Protein and Protein-Lipid Interactions
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