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Research ArticleMinireview

The Complexities of Interpreting Reversible Elevated Serum Creatinine Levels in Drug Development: Does a Correlation with Inhibition of Renal Transporters Exist?

Xiaoyan Chu, Kelly Bleasby, Grace Hoyee Chan, Irene Nunes and Raymond Evers
Drug Metabolism and Disposition September 2016, 44 (9) 1498-1509; DOI: https://doi.org/10.1124/dmd.115.067694
Xiaoyan Chu
Department of Pharmacokinetics, Pharmacodynamics and Drug Metabolism (X.C., K.B., G.H.C., R.E.), and Global Regulatory Affairs, Oncology, Immunology, Biologics & Devices (I.N.), Merck Sharp & Dohme Corporation, Kenilworth, New Jersey
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Kelly Bleasby
Department of Pharmacokinetics, Pharmacodynamics and Drug Metabolism (X.C., K.B., G.H.C., R.E.), and Global Regulatory Affairs, Oncology, Immunology, Biologics & Devices (I.N.), Merck Sharp & Dohme Corporation, Kenilworth, New Jersey
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Grace Hoyee Chan
Department of Pharmacokinetics, Pharmacodynamics and Drug Metabolism (X.C., K.B., G.H.C., R.E.), and Global Regulatory Affairs, Oncology, Immunology, Biologics & Devices (I.N.), Merck Sharp & Dohme Corporation, Kenilworth, New Jersey
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Irene Nunes
Department of Pharmacokinetics, Pharmacodynamics and Drug Metabolism (X.C., K.B., G.H.C., R.E.), and Global Regulatory Affairs, Oncology, Immunology, Biologics & Devices (I.N.), Merck Sharp & Dohme Corporation, Kenilworth, New Jersey
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Raymond Evers
Department of Pharmacokinetics, Pharmacodynamics and Drug Metabolism (X.C., K.B., G.H.C., R.E.), and Global Regulatory Affairs, Oncology, Immunology, Biologics & Devices (I.N.), Merck Sharp & Dohme Corporation, Kenilworth, New Jersey
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Abstract

In humans, creatinine is formed by a multistep process in liver and muscle and eliminated via the kidney by a combination of glomerular filtration and active transport. Based on current evidence, creatinine can be taken up into renal proximal tubule cells by the basolaterally localized organic cation transporter 2 (OCT2) and the organic anion transporter 2, and effluxed into the urine by the apically localized multidrug and toxin extrusion protein 1 (MATE1) and MATE2K. Drug-induced elevation of serum creatinine (SCr) and/or reduced creatinine renal clearance is routinely used as a marker for acute kidney injury. Interpretation of elevated SCr can be complex, because such increases can be reversible and explained by inhibition of renal transporters involved in active secretion of creatinine or other secondary factors, such as diet and disease state. Distinction between these possibilities is important from a drug development perspective, as increases in SCr can result in the termination of otherwise efficacious drug candidates. In this review, we discuss the challenges associated with using creatinine as a marker for kidney damage. Furthermore, to evaluate whether reversible changes in SCr can be predicted prospectively based on in vitro transporter inhibition data, an in-depth in vitro–in vivo correlation (IVIVC) analysis was conducted for 16 drugs with in-house and literature in vitro transporter inhibition data for OCT2, MATE1, and MATE2K, as well as total and unbound maximum plasma concentration (Cmax and Cmax,u) data measured in the clinic.

Footnotes

    • Received October 6, 2015.
    • Accepted January 28, 2016.
  • dx.doi.org/10.1124/dmd.115.067694.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 44 (9)
Drug Metabolism and Disposition
Vol. 44, Issue 9
1 Sep 2016
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Research ArticleMinireview

Serum Creatinine and Inhibition of Renal Transporters

Xiaoyan Chu, Kelly Bleasby, Grace Hoyee Chan, Irene Nunes and Raymond Evers
Drug Metabolism and Disposition September 1, 2016, 44 (9) 1498-1509; DOI: https://doi.org/10.1124/dmd.115.067694

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Research ArticleMinireview

Serum Creatinine and Inhibition of Renal Transporters

Xiaoyan Chu, Kelly Bleasby, Grace Hoyee Chan, Irene Nunes and Raymond Evers
Drug Metabolism and Disposition September 1, 2016, 44 (9) 1498-1509; DOI: https://doi.org/10.1124/dmd.115.067694
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  • Article
    • Abstract
    • Introduction
    • Markers of Renal Function
    • Biosynthesis and Disposition of Creatinine
    • Mathematical Concepts of Renal Clearance of Creatinine
    • Transporters Involved in Active Renal Secretion of Creatinine
    • Inhibition of Renal Transporters and Elevation of SCr: An In Vitro–In Vivo Correlation Analysis
    • Conclusions
    • Acknowledgments
    • Authorship Contributions
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