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Research ArticleMinireview

Drug Concentration Asymmetry in Tissues and Plasma for Small Molecule–Related Therapeutic Modalities

Donglu Zhang, Cornelis E.C.A. Hop, Gabriela Patilea-Vrana, Gautham Gampa, Herana Kamal Seneviratne, Jashvant D. Unadkat, Jane R. Kenny, Karthik Nagapudi, Li Di, Lian Zhou, Mark Zak, Matthew R. Wright, Namandjé N. Bumpus, Richard Zang, Xingrong Liu, Yurong Lai and S. Cyrus Khojasteh
Drug Metabolism and Disposition October 2019, 47 (10) 1122-1135; DOI: https://doi.org/10.1124/dmd.119.086744
Donglu Zhang
Genentech, South San Francisco, California (D.Z., C.E.C.A.H., J.R.K., K.N., M.Z., M.R.W., R.Z., S.C.K.); Department of Medicine, Division of Clinical Pharmacology, The Johns Hopkins University School of Medicine, Baltimore, Maryland (H.K.S., N.N.B.); Brain Barriers Research Center, Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (G.G.); Department of Pharmaceutics, University of Washington, Seattle, Washington (G.P.-V., J.D.U.); Biogen, Cambridge, Massachusetts (X.L.); Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Eastern Point Road, Groton, Connecticut (L.D.); Drug Disposition, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana (L.Z.); and Drug Metabolism, Gilead Sciences, Foster City, California (Y.L.)
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Cornelis E.C.A. Hop
Genentech, South San Francisco, California (D.Z., C.E.C.A.H., J.R.K., K.N., M.Z., M.R.W., R.Z., S.C.K.); Department of Medicine, Division of Clinical Pharmacology, The Johns Hopkins University School of Medicine, Baltimore, Maryland (H.K.S., N.N.B.); Brain Barriers Research Center, Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (G.G.); Department of Pharmaceutics, University of Washington, Seattle, Washington (G.P.-V., J.D.U.); Biogen, Cambridge, Massachusetts (X.L.); Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Eastern Point Road, Groton, Connecticut (L.D.); Drug Disposition, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana (L.Z.); and Drug Metabolism, Gilead Sciences, Foster City, California (Y.L.)
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Gabriela Patilea-Vrana
Genentech, South San Francisco, California (D.Z., C.E.C.A.H., J.R.K., K.N., M.Z., M.R.W., R.Z., S.C.K.); Department of Medicine, Division of Clinical Pharmacology, The Johns Hopkins University School of Medicine, Baltimore, Maryland (H.K.S., N.N.B.); Brain Barriers Research Center, Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (G.G.); Department of Pharmaceutics, University of Washington, Seattle, Washington (G.P.-V., J.D.U.); Biogen, Cambridge, Massachusetts (X.L.); Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Eastern Point Road, Groton, Connecticut (L.D.); Drug Disposition, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana (L.Z.); and Drug Metabolism, Gilead Sciences, Foster City, California (Y.L.)
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Gautham Gampa
Genentech, South San Francisco, California (D.Z., C.E.C.A.H., J.R.K., K.N., M.Z., M.R.W., R.Z., S.C.K.); Department of Medicine, Division of Clinical Pharmacology, The Johns Hopkins University School of Medicine, Baltimore, Maryland (H.K.S., N.N.B.); Brain Barriers Research Center, Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (G.G.); Department of Pharmaceutics, University of Washington, Seattle, Washington (G.P.-V., J.D.U.); Biogen, Cambridge, Massachusetts (X.L.); Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Eastern Point Road, Groton, Connecticut (L.D.); Drug Disposition, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana (L.Z.); and Drug Metabolism, Gilead Sciences, Foster City, California (Y.L.)
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Herana Kamal Seneviratne
Genentech, South San Francisco, California (D.Z., C.E.C.A.H., J.R.K., K.N., M.Z., M.R.W., R.Z., S.C.K.); Department of Medicine, Division of Clinical Pharmacology, The Johns Hopkins University School of Medicine, Baltimore, Maryland (H.K.S., N.N.B.); Brain Barriers Research Center, Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (G.G.); Department of Pharmaceutics, University of Washington, Seattle, Washington (G.P.-V., J.D.U.); Biogen, Cambridge, Massachusetts (X.L.); Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Eastern Point Road, Groton, Connecticut (L.D.); Drug Disposition, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana (L.Z.); and Drug Metabolism, Gilead Sciences, Foster City, California (Y.L.)
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Jashvant D. Unadkat
Genentech, South San Francisco, California (D.Z., C.E.C.A.H., J.R.K., K.N., M.Z., M.R.W., R.Z., S.C.K.); Department of Medicine, Division of Clinical Pharmacology, The Johns Hopkins University School of Medicine, Baltimore, Maryland (H.K.S., N.N.B.); Brain Barriers Research Center, Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (G.G.); Department of Pharmaceutics, University of Washington, Seattle, Washington (G.P.-V., J.D.U.); Biogen, Cambridge, Massachusetts (X.L.); Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Eastern Point Road, Groton, Connecticut (L.D.); Drug Disposition, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana (L.Z.); and Drug Metabolism, Gilead Sciences, Foster City, California (Y.L.)
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Jane R. Kenny
Genentech, South San Francisco, California (D.Z., C.E.C.A.H., J.R.K., K.N., M.Z., M.R.W., R.Z., S.C.K.); Department of Medicine, Division of Clinical Pharmacology, The Johns Hopkins University School of Medicine, Baltimore, Maryland (H.K.S., N.N.B.); Brain Barriers Research Center, Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (G.G.); Department of Pharmaceutics, University of Washington, Seattle, Washington (G.P.-V., J.D.U.); Biogen, Cambridge, Massachusetts (X.L.); Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Eastern Point Road, Groton, Connecticut (L.D.); Drug Disposition, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana (L.Z.); and Drug Metabolism, Gilead Sciences, Foster City, California (Y.L.)
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Karthik Nagapudi
Genentech, South San Francisco, California (D.Z., C.E.C.A.H., J.R.K., K.N., M.Z., M.R.W., R.Z., S.C.K.); Department of Medicine, Division of Clinical Pharmacology, The Johns Hopkins University School of Medicine, Baltimore, Maryland (H.K.S., N.N.B.); Brain Barriers Research Center, Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (G.G.); Department of Pharmaceutics, University of Washington, Seattle, Washington (G.P.-V., J.D.U.); Biogen, Cambridge, Massachusetts (X.L.); Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Eastern Point Road, Groton, Connecticut (L.D.); Drug Disposition, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana (L.Z.); and Drug Metabolism, Gilead Sciences, Foster City, California (Y.L.)
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Li Di
Genentech, South San Francisco, California (D.Z., C.E.C.A.H., J.R.K., K.N., M.Z., M.R.W., R.Z., S.C.K.); Department of Medicine, Division of Clinical Pharmacology, The Johns Hopkins University School of Medicine, Baltimore, Maryland (H.K.S., N.N.B.); Brain Barriers Research Center, Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (G.G.); Department of Pharmaceutics, University of Washington, Seattle, Washington (G.P.-V., J.D.U.); Biogen, Cambridge, Massachusetts (X.L.); Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Eastern Point Road, Groton, Connecticut (L.D.); Drug Disposition, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana (L.Z.); and Drug Metabolism, Gilead Sciences, Foster City, California (Y.L.)
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Lian Zhou
Genentech, South San Francisco, California (D.Z., C.E.C.A.H., J.R.K., K.N., M.Z., M.R.W., R.Z., S.C.K.); Department of Medicine, Division of Clinical Pharmacology, The Johns Hopkins University School of Medicine, Baltimore, Maryland (H.K.S., N.N.B.); Brain Barriers Research Center, Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (G.G.); Department of Pharmaceutics, University of Washington, Seattle, Washington (G.P.-V., J.D.U.); Biogen, Cambridge, Massachusetts (X.L.); Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Eastern Point Road, Groton, Connecticut (L.D.); Drug Disposition, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana (L.Z.); and Drug Metabolism, Gilead Sciences, Foster City, California (Y.L.)
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Mark Zak
Genentech, South San Francisco, California (D.Z., C.E.C.A.H., J.R.K., K.N., M.Z., M.R.W., R.Z., S.C.K.); Department of Medicine, Division of Clinical Pharmacology, The Johns Hopkins University School of Medicine, Baltimore, Maryland (H.K.S., N.N.B.); Brain Barriers Research Center, Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (G.G.); Department of Pharmaceutics, University of Washington, Seattle, Washington (G.P.-V., J.D.U.); Biogen, Cambridge, Massachusetts (X.L.); Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Eastern Point Road, Groton, Connecticut (L.D.); Drug Disposition, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana (L.Z.); and Drug Metabolism, Gilead Sciences, Foster City, California (Y.L.)
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Matthew R. Wright
Genentech, South San Francisco, California (D.Z., C.E.C.A.H., J.R.K., K.N., M.Z., M.R.W., R.Z., S.C.K.); Department of Medicine, Division of Clinical Pharmacology, The Johns Hopkins University School of Medicine, Baltimore, Maryland (H.K.S., N.N.B.); Brain Barriers Research Center, Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (G.G.); Department of Pharmaceutics, University of Washington, Seattle, Washington (G.P.-V., J.D.U.); Biogen, Cambridge, Massachusetts (X.L.); Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Eastern Point Road, Groton, Connecticut (L.D.); Drug Disposition, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana (L.Z.); and Drug Metabolism, Gilead Sciences, Foster City, California (Y.L.)
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Namandjé N. Bumpus
Genentech, South San Francisco, California (D.Z., C.E.C.A.H., J.R.K., K.N., M.Z., M.R.W., R.Z., S.C.K.); Department of Medicine, Division of Clinical Pharmacology, The Johns Hopkins University School of Medicine, Baltimore, Maryland (H.K.S., N.N.B.); Brain Barriers Research Center, Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (G.G.); Department of Pharmaceutics, University of Washington, Seattle, Washington (G.P.-V., J.D.U.); Biogen, Cambridge, Massachusetts (X.L.); Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Eastern Point Road, Groton, Connecticut (L.D.); Drug Disposition, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana (L.Z.); and Drug Metabolism, Gilead Sciences, Foster City, California (Y.L.)
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Richard Zang
Genentech, South San Francisco, California (D.Z., C.E.C.A.H., J.R.K., K.N., M.Z., M.R.W., R.Z., S.C.K.); Department of Medicine, Division of Clinical Pharmacology, The Johns Hopkins University School of Medicine, Baltimore, Maryland (H.K.S., N.N.B.); Brain Barriers Research Center, Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (G.G.); Department of Pharmaceutics, University of Washington, Seattle, Washington (G.P.-V., J.D.U.); Biogen, Cambridge, Massachusetts (X.L.); Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Eastern Point Road, Groton, Connecticut (L.D.); Drug Disposition, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana (L.Z.); and Drug Metabolism, Gilead Sciences, Foster City, California (Y.L.)
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Xingrong Liu
Genentech, South San Francisco, California (D.Z., C.E.C.A.H., J.R.K., K.N., M.Z., M.R.W., R.Z., S.C.K.); Department of Medicine, Division of Clinical Pharmacology, The Johns Hopkins University School of Medicine, Baltimore, Maryland (H.K.S., N.N.B.); Brain Barriers Research Center, Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (G.G.); Department of Pharmaceutics, University of Washington, Seattle, Washington (G.P.-V., J.D.U.); Biogen, Cambridge, Massachusetts (X.L.); Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Eastern Point Road, Groton, Connecticut (L.D.); Drug Disposition, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana (L.Z.); and Drug Metabolism, Gilead Sciences, Foster City, California (Y.L.)
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Yurong Lai
Genentech, South San Francisco, California (D.Z., C.E.C.A.H., J.R.K., K.N., M.Z., M.R.W., R.Z., S.C.K.); Department of Medicine, Division of Clinical Pharmacology, The Johns Hopkins University School of Medicine, Baltimore, Maryland (H.K.S., N.N.B.); Brain Barriers Research Center, Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (G.G.); Department of Pharmaceutics, University of Washington, Seattle, Washington (G.P.-V., J.D.U.); Biogen, Cambridge, Massachusetts (X.L.); Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Eastern Point Road, Groton, Connecticut (L.D.); Drug Disposition, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana (L.Z.); and Drug Metabolism, Gilead Sciences, Foster City, California (Y.L.)
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S. Cyrus Khojasteh
Genentech, South San Francisco, California (D.Z., C.E.C.A.H., J.R.K., K.N., M.Z., M.R.W., R.Z., S.C.K.); Department of Medicine, Division of Clinical Pharmacology, The Johns Hopkins University School of Medicine, Baltimore, Maryland (H.K.S., N.N.B.); Brain Barriers Research Center, Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (G.G.); Department of Pharmaceutics, University of Washington, Seattle, Washington (G.P.-V., J.D.U.); Biogen, Cambridge, Massachusetts (X.L.); Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Eastern Point Road, Groton, Connecticut (L.D.); Drug Disposition, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana (L.Z.); and Drug Metabolism, Gilead Sciences, Foster City, California (Y.L.)
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Drug Metabolism and Disposition: 47 (10)
Drug Metabolism and Disposition
Vol. 47, Issue 10
1 Oct 2019
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Research ArticleMinireview

Tissue Drug Concentrations: Beyond the Free Drug Hypothesis

Donglu Zhang, Cornelis E.C.A. Hop, Gabriela Patilea-Vrana, Gautham Gampa, Herana Kamal Seneviratne, Jashvant D. Unadkat, Jane R. Kenny, Karthik Nagapudi, Li Di, Lian Zhou, Mark Zak, Matthew R. Wright, Namandjé N. Bumpus, Richard Zang, Xingrong Liu, Yurong Lai and S. Cyrus Khojasteh
Drug Metabolism and Disposition October 1, 2019, 47 (10) 1122-1135; DOI: https://doi.org/10.1124/dmd.119.086744

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Research ArticleMinireview

Tissue Drug Concentrations: Beyond the Free Drug Hypothesis

Donglu Zhang, Cornelis E.C.A. Hop, Gabriela Patilea-Vrana, Gautham Gampa, Herana Kamal Seneviratne, Jashvant D. Unadkat, Jane R. Kenny, Karthik Nagapudi, Li Di, Lian Zhou, Mark Zak, Matthew R. Wright, Namandjé N. Bumpus, Richard Zang, Xingrong Liu, Yurong Lai and S. Cyrus Khojasteh
Drug Metabolism and Disposition October 1, 2019, 47 (10) 1122-1135; DOI: https://doi.org/10.1124/dmd.119.086744
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  • Article
    • Abstract
    • Introduction
    • Methods for Determining Total Drug Concentrations in Plasma and Tissues
    • Estimation of Free Drug Concentrations and Kp,uu
    • Cases of Asymmetric Tissue Distribution
    • Summary
    • Acknowledgments
    • Authorship Contributions
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    • Abbreviations
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