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Review ArticleMinireview

Process and System Clearances in Pharmacokinetic Models: Our Basic Clearance Concepts Are Correct

Ken Korzekwa and Swati Nagar
Drug Metabolism and Disposition April 2023, 51 (4) 532-542; DOI: https://doi.org/10.1124/dmd.122.001060
Ken Korzekwa
Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, Pennsylvania
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Swati Nagar
Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, Pennsylvania
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Abstract

Clearances are important parameters in pharmacokinetic (PK) models. All clearances in PK models are either process clearances that include diffusion, transport, and metabolism clearances or system clearances that include organ and systemic clearance. Clearance and volume of distribution are two independent parameters that characterize drug disposition in both individual compartments and systems of compartments. In this minireview, we show that systemic and organ clearances are net clearances that can be easily derived by partition analysis. When drugs are eliminated from the central compartment by first-order processes, systemic clearance is constant. When drugs are eliminated from a peripheral compartment, instantaneous systemic clearance will vary with time. However, average clearance and clearance at steady state will be constant and will equal dose divided by area under the curve. We show that peripheral elimination will not have a large impact on most pharmacokinetic analyses and that standard models of organ and systemic clearance are useful and appropriate.

SIGNIFICANCE STATEMENT There are two basic kinds of clearances used in pharmacokinetic models, process and system clearances. We show that organ and systemic clearances are net clearances with blood or plasma as the driving concentration. For linear pharmacokinetics, clearance is constant for elimination from the central compartment but varies with time for peripheral elimination. Despite the different kinds of clearance parameters and models, standard clearance models and concepts remain valid.

Footnotes

    • Received August 10, 2022.
    • Accepted December 15, 2022.
  • This work was partially funded by National Institutes of Health National Institute of General Medical Sciences [Grant 2R01GM104178] and [Grant 2R01GM114369] for KK and SN.

  • No author has an actual or perceived conflict of interest with the contents of this article.

  • dx.doi.org/10.1124/dmd.122.001060.

  • Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 51 (4)
Drug Metabolism and Disposition
Vol. 51, Issue 4
1 Apr 2023
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Review ArticleMinireview

Clearance Concepts in PK

Ken Korzekwa and Swati Nagar
Drug Metabolism and Disposition April 1, 2023, 51 (4) 532-542; DOI: https://doi.org/10.1124/dmd.122.001060

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Review ArticleMinireview

Clearance Concepts in PK

Ken Korzekwa and Swati Nagar
Drug Metabolism and Disposition April 1, 2023, 51 (4) 532-542; DOI: https://doi.org/10.1124/dmd.122.001060
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