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Research ArticleArticle

Intersystem Extrapolation Factors Are Substrate-Dependent for CYP3A4: Impact on Cytochrome P450 Reaction Phenotyping

Alyssa L. Dantonio, Angela C. Doran and R. Scott Obach
Drug Metabolism and Disposition March 2022, 50 (3) 249-257; DOI: https://doi.org/10.1124/dmd.121.000758
Alyssa L. Dantonio
Pfizer, Inc., Groton, Connecticut
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Angela C. Doran
Pfizer, Inc., Groton, Connecticut
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R. Scott Obach
Pfizer, Inc., Groton, Connecticut
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Abstract

The use of intersystem extrapolation factors (ISEF) is required for the quantitative scaling of drug metabolism data generated in individually expressed cytochrome P450 (CYP) enzymes when estimating fractional contribution (fm) to metabolism by P450 enzymes in vivo. For successful prediction of fm, ISEF values must be universal across all substrates for any individual enzyme. In this study, ISEF values were generated for ten CYP3A4 selective substrates using a common source of recombinant heterologously expressed CYP3A4 (rCYP) and a pool of human liver microsomes. The resulting ISEF values for CYP3A4 were substrate-dependent and ranged 8-fold, with the highest value generated from intrinsic clearance of midazolam depletion (0.36) and the lowest from quinidine depletion (0.044). Application of these ISEF values for estimation of the fractional contribution of CYP3A4 and CYP2C19 to omeprazole clearance yielded values that ranged from 0.21–0.63 and 0.37–0.79, respectively, as compared with back-extrapolated in vivo fm values of 0.27 (CYP3A4) and 0.85 (CYP2C19) from clinical pharmacokinetic data. For risperidone, estimated fm values for CYP3A4 and CYP2D6 ranged from 0.87–0.98 and 0.02–0.13, respectively, as compared with in vivo values of 0.36 (CYP3A4) and 0.63–0.88 (CYP2D6), showing that the importance of CYP3A4 was overestimated, and the importance of CYP2D6 underestimated. Overall, these findings suggest that ISEF values for CYP3A4 can vary with the marker substrate used to derive them, thereby reducing the effectiveness of the approach of using metabolism data from rCYP3A4 with ISEF values for the prediction of fraction metabolized values in vivo.

SIGNIFICANCE STATEMENT Intersystem extrapolation factors are utilized for assigning fractional contributions of individual enzymes to drug clearance (fm) from drug metabolism data generated in recombinant P450s. The present data shows that intersystem extrapolation factors values for cytochrome P4503A4 vary with the substrate. This can lead to variable and erroneous prediction of fm.

Footnotes

    • Received October 30, 2021.
    • Accepted December 6, 2021.
  • This paper received no external funding.

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

  • https://dx.doi.org/10.1124/dmd.121.000758.

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

  • Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 50 (3)
Drug Metabolism and Disposition
Vol. 50, Issue 3
1 Mar 2022
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Research ArticleArticle

ISEF for Cytochrome P4503A4

Alyssa L. Dantonio, Angela C. Doran and R. Scott Obach
Drug Metabolism and Disposition March 1, 2022, 50 (3) 249-257; DOI: https://doi.org/10.1124/dmd.121.000758

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Research ArticleArticle

ISEF for Cytochrome P4503A4

Alyssa L. Dantonio, Angela C. Doran and R. Scott Obach
Drug Metabolism and Disposition March 1, 2022, 50 (3) 249-257; DOI: https://doi.org/10.1124/dmd.121.000758
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