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Research ArticleSpecial Section on Prediction of Human Pharmacokinetic Parameters from In Vitro Systems

Heterotropic Activation of the Midazolam Hydroxylase Activity of CYP3A by a Positive Allosteric Modulator of mGlu5: In Vitro to In Vivo Translation and Potential Impact on Clinically Relevant Drug-Drug Interactions

Anna L. Blobaum, Thomas M. Bridges, Frank W. Byers, Mark L. Turlington, Margrith E. Mattmann, Ryan D. Morrison, Claire Mackie, Hilde Lavreysen, José M. Bartolomé, Gregor J. MacDonald, Thomas Steckler, Carrie K. Jones, Colleen M. Niswender, P. Jeffrey Conn, Craig W. Lindsley, Shaun R. Stauffer and J. Scott Daniels
Drug Metabolism and Disposition December 2013, 41 (12) 2066-2075; DOI: https://doi.org/10.1124/dmd.113.052662
Anna L. Blobaum
Drug Metabolism and Pharmacokinetics Laboratory (A.L.B., T.M.B., F.W.B., R.D.M., J.S.D.), Medicinal Chemistry Laboratory (M.L.T., M.E.M., C.W.L., S.R.S.), and Molecular Pharmacology Laboratory (C.K.J., C.M.N., P.J.C.), Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, Tennessee; CREATe ADME/Tox, (C.M.), and Neuroscience (H.L., G.J.M., T.S.), Janssen Research and Development, Beerse, Belgium; and Jarama 75, Toledo, Spain (J.M.B.)
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Thomas M. Bridges
Drug Metabolism and Pharmacokinetics Laboratory (A.L.B., T.M.B., F.W.B., R.D.M., J.S.D.), Medicinal Chemistry Laboratory (M.L.T., M.E.M., C.W.L., S.R.S.), and Molecular Pharmacology Laboratory (C.K.J., C.M.N., P.J.C.), Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, Tennessee; CREATe ADME/Tox, (C.M.), and Neuroscience (H.L., G.J.M., T.S.), Janssen Research and Development, Beerse, Belgium; and Jarama 75, Toledo, Spain (J.M.B.)
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Frank W. Byers
Drug Metabolism and Pharmacokinetics Laboratory (A.L.B., T.M.B., F.W.B., R.D.M., J.S.D.), Medicinal Chemistry Laboratory (M.L.T., M.E.M., C.W.L., S.R.S.), and Molecular Pharmacology Laboratory (C.K.J., C.M.N., P.J.C.), Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, Tennessee; CREATe ADME/Tox, (C.M.), and Neuroscience (H.L., G.J.M., T.S.), Janssen Research and Development, Beerse, Belgium; and Jarama 75, Toledo, Spain (J.M.B.)
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Mark L. Turlington
Drug Metabolism and Pharmacokinetics Laboratory (A.L.B., T.M.B., F.W.B., R.D.M., J.S.D.), Medicinal Chemistry Laboratory (M.L.T., M.E.M., C.W.L., S.R.S.), and Molecular Pharmacology Laboratory (C.K.J., C.M.N., P.J.C.), Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, Tennessee; CREATe ADME/Tox, (C.M.), and Neuroscience (H.L., G.J.M., T.S.), Janssen Research and Development, Beerse, Belgium; and Jarama 75, Toledo, Spain (J.M.B.)
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Margrith E. Mattmann
Drug Metabolism and Pharmacokinetics Laboratory (A.L.B., T.M.B., F.W.B., R.D.M., J.S.D.), Medicinal Chemistry Laboratory (M.L.T., M.E.M., C.W.L., S.R.S.), and Molecular Pharmacology Laboratory (C.K.J., C.M.N., P.J.C.), Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, Tennessee; CREATe ADME/Tox, (C.M.), and Neuroscience (H.L., G.J.M., T.S.), Janssen Research and Development, Beerse, Belgium; and Jarama 75, Toledo, Spain (J.M.B.)
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Ryan D. Morrison
Drug Metabolism and Pharmacokinetics Laboratory (A.L.B., T.M.B., F.W.B., R.D.M., J.S.D.), Medicinal Chemistry Laboratory (M.L.T., M.E.M., C.W.L., S.R.S.), and Molecular Pharmacology Laboratory (C.K.J., C.M.N., P.J.C.), Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, Tennessee; CREATe ADME/Tox, (C.M.), and Neuroscience (H.L., G.J.M., T.S.), Janssen Research and Development, Beerse, Belgium; and Jarama 75, Toledo, Spain (J.M.B.)
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Claire Mackie
Drug Metabolism and Pharmacokinetics Laboratory (A.L.B., T.M.B., F.W.B., R.D.M., J.S.D.), Medicinal Chemistry Laboratory (M.L.T., M.E.M., C.W.L., S.R.S.), and Molecular Pharmacology Laboratory (C.K.J., C.M.N., P.J.C.), Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, Tennessee; CREATe ADME/Tox, (C.M.), and Neuroscience (H.L., G.J.M., T.S.), Janssen Research and Development, Beerse, Belgium; and Jarama 75, Toledo, Spain (J.M.B.)
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Hilde Lavreysen
Drug Metabolism and Pharmacokinetics Laboratory (A.L.B., T.M.B., F.W.B., R.D.M., J.S.D.), Medicinal Chemistry Laboratory (M.L.T., M.E.M., C.W.L., S.R.S.), and Molecular Pharmacology Laboratory (C.K.J., C.M.N., P.J.C.), Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, Tennessee; CREATe ADME/Tox, (C.M.), and Neuroscience (H.L., G.J.M., T.S.), Janssen Research and Development, Beerse, Belgium; and Jarama 75, Toledo, Spain (J.M.B.)
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José M. Bartolomé
Drug Metabolism and Pharmacokinetics Laboratory (A.L.B., T.M.B., F.W.B., R.D.M., J.S.D.), Medicinal Chemistry Laboratory (M.L.T., M.E.M., C.W.L., S.R.S.), and Molecular Pharmacology Laboratory (C.K.J., C.M.N., P.J.C.), Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, Tennessee; CREATe ADME/Tox, (C.M.), and Neuroscience (H.L., G.J.M., T.S.), Janssen Research and Development, Beerse, Belgium; and Jarama 75, Toledo, Spain (J.M.B.)
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Gregor J. MacDonald
Drug Metabolism and Pharmacokinetics Laboratory (A.L.B., T.M.B., F.W.B., R.D.M., J.S.D.), Medicinal Chemistry Laboratory (M.L.T., M.E.M., C.W.L., S.R.S.), and Molecular Pharmacology Laboratory (C.K.J., C.M.N., P.J.C.), Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, Tennessee; CREATe ADME/Tox, (C.M.), and Neuroscience (H.L., G.J.M., T.S.), Janssen Research and Development, Beerse, Belgium; and Jarama 75, Toledo, Spain (J.M.B.)
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Thomas Steckler
Drug Metabolism and Pharmacokinetics Laboratory (A.L.B., T.M.B., F.W.B., R.D.M., J.S.D.), Medicinal Chemistry Laboratory (M.L.T., M.E.M., C.W.L., S.R.S.), and Molecular Pharmacology Laboratory (C.K.J., C.M.N., P.J.C.), Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, Tennessee; CREATe ADME/Tox, (C.M.), and Neuroscience (H.L., G.J.M., T.S.), Janssen Research and Development, Beerse, Belgium; and Jarama 75, Toledo, Spain (J.M.B.)
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Carrie K. Jones
Drug Metabolism and Pharmacokinetics Laboratory (A.L.B., T.M.B., F.W.B., R.D.M., J.S.D.), Medicinal Chemistry Laboratory (M.L.T., M.E.M., C.W.L., S.R.S.), and Molecular Pharmacology Laboratory (C.K.J., C.M.N., P.J.C.), Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, Tennessee; CREATe ADME/Tox, (C.M.), and Neuroscience (H.L., G.J.M., T.S.), Janssen Research and Development, Beerse, Belgium; and Jarama 75, Toledo, Spain (J.M.B.)
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Colleen M. Niswender
Drug Metabolism and Pharmacokinetics Laboratory (A.L.B., T.M.B., F.W.B., R.D.M., J.S.D.), Medicinal Chemistry Laboratory (M.L.T., M.E.M., C.W.L., S.R.S.), and Molecular Pharmacology Laboratory (C.K.J., C.M.N., P.J.C.), Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, Tennessee; CREATe ADME/Tox, (C.M.), and Neuroscience (H.L., G.J.M., T.S.), Janssen Research and Development, Beerse, Belgium; and Jarama 75, Toledo, Spain (J.M.B.)
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P. Jeffrey Conn
Drug Metabolism and Pharmacokinetics Laboratory (A.L.B., T.M.B., F.W.B., R.D.M., J.S.D.), Medicinal Chemistry Laboratory (M.L.T., M.E.M., C.W.L., S.R.S.), and Molecular Pharmacology Laboratory (C.K.J., C.M.N., P.J.C.), Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, Tennessee; CREATe ADME/Tox, (C.M.), and Neuroscience (H.L., G.J.M., T.S.), Janssen Research and Development, Beerse, Belgium; and Jarama 75, Toledo, Spain (J.M.B.)
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Craig W. Lindsley
Drug Metabolism and Pharmacokinetics Laboratory (A.L.B., T.M.B., F.W.B., R.D.M., J.S.D.), Medicinal Chemistry Laboratory (M.L.T., M.E.M., C.W.L., S.R.S.), and Molecular Pharmacology Laboratory (C.K.J., C.M.N., P.J.C.), Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, Tennessee; CREATe ADME/Tox, (C.M.), and Neuroscience (H.L., G.J.M., T.S.), Janssen Research and Development, Beerse, Belgium; and Jarama 75, Toledo, Spain (J.M.B.)
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Shaun R. Stauffer
Drug Metabolism and Pharmacokinetics Laboratory (A.L.B., T.M.B., F.W.B., R.D.M., J.S.D.), Medicinal Chemistry Laboratory (M.L.T., M.E.M., C.W.L., S.R.S.), and Molecular Pharmacology Laboratory (C.K.J., C.M.N., P.J.C.), Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, Tennessee; CREATe ADME/Tox, (C.M.), and Neuroscience (H.L., G.J.M., T.S.), Janssen Research and Development, Beerse, Belgium; and Jarama 75, Toledo, Spain (J.M.B.)
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J. Scott Daniels
Drug Metabolism and Pharmacokinetics Laboratory (A.L.B., T.M.B., F.W.B., R.D.M., J.S.D.), Medicinal Chemistry Laboratory (M.L.T., M.E.M., C.W.L., S.R.S.), and Molecular Pharmacology Laboratory (C.K.J., C.M.N., P.J.C.), Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, Tennessee; CREATe ADME/Tox, (C.M.), and Neuroscience (H.L., G.J.M., T.S.), Janssen Research and Development, Beerse, Belgium; and Jarama 75, Toledo, Spain (J.M.B.)
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Article Information

vol. 41 no. 12 2066-2075
DOI 
https://doi.org/10.1124/dmd.113.052662
PubMed 
24003250

Published By 
American Society for Pharmacology and Experimental Therapeutics
Print ISSN 
0090-9556
Online ISSN 
1521-009X
History 
  • Received May 2, 2013
  • Accepted August 30, 2013
  • Published online November 14, 2013.

Article Versions

  • Earlier version (September 3, 2013 - 11:23).
  • You are viewing the most recent version of this article.
Copyright & Usage 
Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics

Author Information

  1. Anna L. Blobaum,
  2. Thomas M. Bridges,
  3. Frank W. Byers,
  4. Mark L. Turlington,
  5. Margrith E. Mattmann,
  6. Ryan D. Morrison,
  7. Claire Mackie,
  8. Hilde Lavreysen,
  9. José M. Bartolomé,
  10. Gregor J. MacDonald,
  11. Thomas Steckler,
  12. Carrie K. Jones,
  13. Colleen M. Niswender,
  14. P. Jeffrey Conn,
  15. Craig W. Lindsley,
  16. Shaun R. Stauffer, and
  17. J. Scott Daniels
  1. Drug Metabolism and Pharmacokinetics Laboratory (A.L.B., T.M.B., F.W.B., R.D.M., J.S.D.), Medicinal Chemistry Laboratory (M.L.T., M.E.M., C.W.L., S.R.S.), and Molecular Pharmacology Laboratory (C.K.J., C.M.N., P.J.C.), Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, Tennessee; CREATe ADME/Tox, (C.M.), and Neuroscience (H.L., G.J.M., T.S.), Janssen Research and Development, Beerse, Belgium; and Jarama 75, Toledo, Spain (J.M.B.)
  1. Address correspondence to:
    Dr. J. Scott Daniels, Drug Metabolism and Pharmacokinetics Laboratory, Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232. E-mail: scott.daniels{at}vanderbilt.edu
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Drug Metabolism and Disposition: 41 (12)
Drug Metabolism and Disposition
Vol. 41, Issue 12
1 Dec 2013
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Heterotropic Activation of the Midazolam Hydroxylase Activity of CYP3A by a Positive Allosteric Modulator of mGlu5: In Vitro to In Vivo Translation and Potential Impact on Clinically Relevant Drug-Drug Interactions
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Research ArticleSpecial Section on Prediction of Human Pharmacokinetic Parameters from In Vitro Systems

Heterotropic Activation of CYP3A by a Novel mGlu5 PAM

Anna L. Blobaum, Thomas M. Bridges, Frank W. Byers, Mark L. Turlington, Margrith E. Mattmann, Ryan D. Morrison, Claire Mackie, Hilde Lavreysen, José M. Bartolomé, Gregor J. MacDonald, Thomas Steckler, Carrie K. Jones, Colleen M. Niswender, P. Jeffrey Conn, Craig W. Lindsley, Shaun R. Stauffer and J. Scott Daniels
Drug Metabolism and Disposition December 1, 2013, 41 (12) 2066-2075; DOI: https://doi.org/10.1124/dmd.113.052662

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Research ArticleSpecial Section on Prediction of Human Pharmacokinetic Parameters from In Vitro Systems

Heterotropic Activation of CYP3A by a Novel mGlu5 PAM

Anna L. Blobaum, Thomas M. Bridges, Frank W. Byers, Mark L. Turlington, Margrith E. Mattmann, Ryan D. Morrison, Claire Mackie, Hilde Lavreysen, José M. Bartolomé, Gregor J. MacDonald, Thomas Steckler, Carrie K. Jones, Colleen M. Niswender, P. Jeffrey Conn, Craig W. Lindsley, Shaun R. Stauffer and J. Scott Daniels
Drug Metabolism and Disposition December 1, 2013, 41 (12) 2066-2075; DOI: https://doi.org/10.1124/dmd.113.052662
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