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Research ArticleArticle

The Reliability of Estimating Ki Values for Direct, Reversible Inhibition of Cytochrome P450 Enzymes from Corresponding IC50 Values: A Retrospective Analysis of 343 Experiments

Lois J. Haupt, Faraz Kazmi, Brian W. Ogilvie, David B. Buckley, Brian D. Smith, Sarah Leatherman, Brandy Paris, Oliver Parkinson and Andrew Parkinson
Drug Metabolism and Disposition November 2015, 43 (11) 1744-1750; DOI: https://doi.org/10.1124/dmd.115.066597
Lois J. Haupt
XenoTech, LLC, Lenexa, Kansas (L.J.H., F.K., B.W.O., D.B.B., B.D.S., S.L.); and XPD Consulting, Shawnee, Kansas (B.P., O.P., A.P.)
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Faraz Kazmi
XenoTech, LLC, Lenexa, Kansas (L.J.H., F.K., B.W.O., D.B.B., B.D.S., S.L.); and XPD Consulting, Shawnee, Kansas (B.P., O.P., A.P.)
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  • ORCID record for Faraz Kazmi
Brian W. Ogilvie
XenoTech, LLC, Lenexa, Kansas (L.J.H., F.K., B.W.O., D.B.B., B.D.S., S.L.); and XPD Consulting, Shawnee, Kansas (B.P., O.P., A.P.)
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David B. Buckley
XenoTech, LLC, Lenexa, Kansas (L.J.H., F.K., B.W.O., D.B.B., B.D.S., S.L.); and XPD Consulting, Shawnee, Kansas (B.P., O.P., A.P.)
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Brian D. Smith
XenoTech, LLC, Lenexa, Kansas (L.J.H., F.K., B.W.O., D.B.B., B.D.S., S.L.); and XPD Consulting, Shawnee, Kansas (B.P., O.P., A.P.)
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Sarah Leatherman
XenoTech, LLC, Lenexa, Kansas (L.J.H., F.K., B.W.O., D.B.B., B.D.S., S.L.); and XPD Consulting, Shawnee, Kansas (B.P., O.P., A.P.)
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Brandy Paris
XenoTech, LLC, Lenexa, Kansas (L.J.H., F.K., B.W.O., D.B.B., B.D.S., S.L.); and XPD Consulting, Shawnee, Kansas (B.P., O.P., A.P.)
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Oliver Parkinson
XenoTech, LLC, Lenexa, Kansas (L.J.H., F.K., B.W.O., D.B.B., B.D.S., S.L.); and XPD Consulting, Shawnee, Kansas (B.P., O.P., A.P.)
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Andrew Parkinson
XenoTech, LLC, Lenexa, Kansas (L.J.H., F.K., B.W.O., D.B.B., B.D.S., S.L.); and XPD Consulting, Shawnee, Kansas (B.P., O.P., A.P.)
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Abstract

In the present study, we conducted a retrospective analysis of 343 in vitro experiments to ascertain whether observed (experimentally determined) values of Ki for reversible cytochrome P450 (P450) inhibition could be reliably predicted by dividing the corresponding IC50 values by two, based on the relationship (for competitive inhibition) in which Ki = IC50/2 when [S] (substrate concentration) = Km (Michaelis-Menten constant). Values of Ki and IC50 were determined under the following conditions: 1) the concentration of P450 marker substrate, [S], was equal to Km (for IC50 determinations) and spanned Km (for Ki determinations); 2) the substrate incubation time was short (5 minutes) to minimize metabolism-dependent inhibition and inhibitor depletion; and 3) the concentration of human liver microsomes was low (0.1 mg/ml or less) to maximize the unbound fraction of inhibitor. Under these conditions, predicted Ki values, based on IC50/2, correlated strongly with experimentally observed Ki determinations [r = 0.940; average fold error (AFE) = 1.10]. Of the 343 predicted Ki values, 316 (92%) were within a factor of 2 of the experimentally determined Ki values, and only one value fell outside a 3-fold range. In the case of noncompetitive inhibitors, Ki values predicted from IC50/2 values were overestimated by a factor of nearly 2 (AFE = 1.85; n = 13), which is to be expected because, for noncompetitive inhibition, Ki = IC50 (not IC50/2). The results suggest that, under appropriate experimental conditions with the substrate concentration equal to Km, values of Ki for direct, reversible inhibition can be reliably estimated from values of IC50/2.

Footnotes

    • Received July 28, 2015.
    • Accepted September 8, 2015.
  • Parts of this work were previously presented at the following meeting: Haupt L, Kazmi F, Ogilvie B, Buckley D, Smith B, Leatherman S, and Parkinson A (2011) Can Ki values for direct inhibition of CYP enzymes be reliably estimated from IC50 values? Seventeenth North American Regional ISSX Meeting; 2011 Oct 16–20; Atlanta, GA.

  • dx.doi.org/10.1124/dmd.115.066597.

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

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 43 (11)
Drug Metabolism and Disposition
Vol. 43, Issue 11
1 Nov 2015
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Research ArticleArticle

Estimating Ki from IC50 Values for P450 Inhibition

Lois J. Haupt, Faraz Kazmi, Brian W. Ogilvie, David B. Buckley, Brian D. Smith, Sarah Leatherman, Brandy Paris, Oliver Parkinson and Andrew Parkinson
Drug Metabolism and Disposition November 1, 2015, 43 (11) 1744-1750; DOI: https://doi.org/10.1124/dmd.115.066597

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Research ArticleArticle

Estimating Ki from IC50 Values for P450 Inhibition

Lois J. Haupt, Faraz Kazmi, Brian W. Ogilvie, David B. Buckley, Brian D. Smith, Sarah Leatherman, Brandy Paris, Oliver Parkinson and Andrew Parkinson
Drug Metabolism and Disposition November 1, 2015, 43 (11) 1744-1750; DOI: https://doi.org/10.1124/dmd.115.066597
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