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Research ArticleSpecial Section on Transporters in Toxicity and Disease

Understanding the Transport Properties of Metabolites: Case Studies and Considerations for Drug Development

Maciej J. Zamek-Gliszczynski, Xiaoyan Chu, Joseph W. Polli, Mary F. Paine and Aleksandra Galetin
Drug Metabolism and Disposition April 2014, 42 (4) 650-664; DOI: https://doi.org/10.1124/dmd.113.055558
Maciej J. Zamek-Gliszczynski
Drug Disposition, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana (M.J.Z.-G.); Department of Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Rahway, New Jersey (X.C.); Drug Metabolism and Pharmacokinetics, GlaxoSmithKline Inc., Research Triangle Park, North Carolina (J.W.P.); College of Pharmacy, Washington State University, Spokane, Washington (M.F.P.); and Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, The University of Manchester, Manchester, United Kingdom (A.G.)
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Xiaoyan Chu
Drug Disposition, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana (M.J.Z.-G.); Department of Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Rahway, New Jersey (X.C.); Drug Metabolism and Pharmacokinetics, GlaxoSmithKline Inc., Research Triangle Park, North Carolina (J.W.P.); College of Pharmacy, Washington State University, Spokane, Washington (M.F.P.); and Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, The University of Manchester, Manchester, United Kingdom (A.G.)
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Joseph W. Polli
Drug Disposition, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana (M.J.Z.-G.); Department of Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Rahway, New Jersey (X.C.); Drug Metabolism and Pharmacokinetics, GlaxoSmithKline Inc., Research Triangle Park, North Carolina (J.W.P.); College of Pharmacy, Washington State University, Spokane, Washington (M.F.P.); and Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, The University of Manchester, Manchester, United Kingdom (A.G.)
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Mary F. Paine
Drug Disposition, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana (M.J.Z.-G.); Department of Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Rahway, New Jersey (X.C.); Drug Metabolism and Pharmacokinetics, GlaxoSmithKline Inc., Research Triangle Park, North Carolina (J.W.P.); College of Pharmacy, Washington State University, Spokane, Washington (M.F.P.); and Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, The University of Manchester, Manchester, United Kingdom (A.G.)
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Aleksandra Galetin
Drug Disposition, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana (M.J.Z.-G.); Department of Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Rahway, New Jersey (X.C.); Drug Metabolism and Pharmacokinetics, GlaxoSmithKline Inc., Research Triangle Park, North Carolina (J.W.P.); College of Pharmacy, Washington State University, Spokane, Washington (M.F.P.); and Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, The University of Manchester, Manchester, United Kingdom (A.G.)
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Abstract

Recent analyses demonstrated that metabolites are unlikely to contribute significantly to clinical inhibition of cytochrome P450 (P450)–mediated drug metabolism, and that only ∼2% of this type of drug interaction could not be predicted from the parent drug alone. Due to generally increased polarity and decreased permeability, metabolites are less likely to interact with P450s, but their disposition is instead more likely to involve transporters. This commentary presents case studies illustrating the potential importance of transporters as determinants of metabolite disposition, and as sites of drug interactions, which may alter drug efficacy and safety. Many of these examples are hydrophilic phase II conjugates involved in enterohepatic cycling, where modulation of transporter-dependent disposition may alter pharmacokinetics/pharmacodynamics. The case studies suggest that characterization of metabolite disposition, toxicology, and pharmacology should not focus solely on metabolites with appreciable systemic exposure, but should take into consideration major excretory metabolites. A more thorough understanding of metabolite (phase I and II; circulating and excreted) transport properties during drug development may provide an improved understanding of complex drug-drug interactions (DDIs) that can alter drug and/or metabolite systemic and intracellular exposure. Knowledge and capability gaps remain in clinical translation of in vitro and animal data regarding metabolite disposition. To this end, useful experimental and modeling approaches are highlighted. Application of these tools may lead to a better understanding of metabolite victim and perpetrator DDI potential, and ultimately the establishment of approaches for prediction of pharmacodynamic and toxicodynamic consequences of metabolite transport modulation.

Footnotes

    • Received October 25, 2013.
    • Accepted December 17, 2013.
  • dx.doi.org/10.1124/dmd.113.055558.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 42 (4)
Drug Metabolism and Disposition
Vol. 42, Issue 4
1 Apr 2014
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Research ArticleSpecial Section on Transporters in Toxicity and Disease

Metabolite Transport in DDIs, Toxicity, and Efficacy

Maciej J. Zamek-Gliszczynski, Xiaoyan Chu, Joseph W. Polli, Mary F. Paine and Aleksandra Galetin
Drug Metabolism and Disposition April 1, 2014, 42 (4) 650-664; DOI: https://doi.org/10.1124/dmd.113.055558

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Research ArticleSpecial Section on Transporters in Toxicity and Disease

Metabolite Transport in DDIs, Toxicity, and Efficacy

Maciej J. Zamek-Gliszczynski, Xiaoyan Chu, Joseph W. Polli, Mary F. Paine and Aleksandra Galetin
Drug Metabolism and Disposition April 1, 2014, 42 (4) 650-664; DOI: https://doi.org/10.1124/dmd.113.055558
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