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Research ArticleArticle

Complex Cytochrome P450 Kinetics Due to Multisubstrate Binding and Sequential Metabolism. Part 1. Theoretical Considerations

Zeyuan Wang, Erickson M. Paragas, Swati Nagar and Ken Korzekwa
Drug Metabolism and Disposition December 2021, 49 (12) 1090-1099; DOI: https://doi.org/10.1124/dmd.121.000553
Zeyuan Wang
Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, Pennsylvania
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Erickson M. Paragas
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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Ken Korzekwa
Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, Pennsylvania
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Abstract

Complexities in P450-mediated metabolism kinetics include multisubstrate binding, multiple-product formation, and sequential metabolism. Saturation curves and intrinsic clearances were simulated for single-substrate and multisubstrate models using derived velocity equations and numerical solutions of ordinary differential equations (ODEs). Multisubstrate models focused on sigmoidal kinetics because of their dramatic impact on clearance predictions. These models were combined with multiple-product formation and sequential metabolism, and simulations were performed with random error. Use of single-substrate models to characterize multisubstrate data can result in inaccurate kinetic parameters and poor clearance predictions. Comparing results for use of standard velocity equations with ODEs clearly shows that ODEs are more versatile and provide better parameter estimates. It would be difficult to derive concentration-velocity relationships for complex models, but these relationships can be easily modeled using numerical methods and ODEs.

SIGNIFICANCE STATEMENT The impact of multisubstrate binding, multiple-product formation, and sequential metabolism on the P450 kinetics was investigated. Numerical methods are capable of characterizing complicated P450 kinetics.

Footnotes

    • Received May 25, 2021.
    • Accepted September 6, 2021.
  • This work was supported by National Institutes of Health National Institute of General Medical Sciences (to K.K. and S.N.) [Grants 2R01GM104178 and 2R01GM114369].

  • The authors have no financial disclosures, and no conflicts of interest to report.

  • ↵1 Z.W. and E.M.P. contributed equally to the work.

  • https://dx.doi.org/10.1124/dmd.121.000553.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 49 (12)
Drug Metabolism and Disposition
Vol. 49, Issue 12
1 Dec 2021
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Research ArticleArticle

Complex P450 Kinetics: Theoretical Considerations

Zeyuan Wang, Erickson M. Paragas, Swati Nagar and Ken Korzekwa
Drug Metabolism and Disposition December 1, 2021, 49 (12) 1090-1099; DOI: https://doi.org/10.1124/dmd.121.000553

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Research ArticleArticle

Complex P450 Kinetics: Theoretical Considerations

Zeyuan Wang, Erickson M. Paragas, Swati Nagar and Ken Korzekwa
Drug Metabolism and Disposition December 1, 2021, 49 (12) 1090-1099; DOI: https://doi.org/10.1124/dmd.121.000553
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