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Research ArticleArticle

Sigmoidal Kinetics of CYP3A Substrates: An Approach for Scaling Dextromethorphan Metabolism in Hepatic Microsomes and Isolated Hepatocytes to Predict In Vivo Clearance in Rat

Lynn E. Witherow and J. Brian Houston
Journal of Pharmacology and Experimental Therapeutics July 1999, 290 (1) 58-65;
Lynn E. Witherow
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J. Brian Houston
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Abstract

The metabolism of a number of compounds by the cytochrome P-450 subfamily CYP3A does not exhibit classic Michaelis-Menten kinetics but displays a sigmoidal rate-substrate concentration relationship. Intrinsic clearance (CLint) cannot be calculated for these drugs due to the lack of a first order region in their kinetic profiles, and a suitable parameter has yet to be identified to allow such data to be scaled to predict in vivo clearance. As sigmoidal kinetics have only been observed with microsomal systems, we have investigated whether this behavior is demonstrable in freshly isolated hepatocytes. We have also evaluated the term maximum clearance (CLmax), which refers to the in vitro clearance when the enzyme is fully activated, to predict in vivo clearance. To these ends we have studied the metabolism of dextromethorphan to methoxymorphinan and dextrorphan; methoxymorphinan production is best described by sigmoidal kinetics in both hepatocytes and microsomes, dextrorphan production is best described by a two site Michaelis-Menten model in microsomes but is sigmoidal in hepatocytes. Total clearance, estimated from the CLmax and CLint terms, was scaled to give mean predictions of 127 to 319 ml/min/standard rat weight of 250 g. In vivo CLint, determined after infusion via the hepatic portal vein to steady state and correcting for plasma protein binding and blood-to-plasma concentration ratio, was 259 ± 59.2 ml/min/standard rat weight of 250 g. These investigations show that sigmoidal kinetics is not unique to microsomes and that CLmax is a useful parameter for scaling to the in vivo situation.

Footnotes

  • Send reprint requests to: Dr. J.B. Houston, School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester M13 9PL, UK. E-mail: bhouston{at}man.ac.uk

  • ↵1 This work was supported by the European Center for the Validation of Alternative Methods (ECVAM) Contract 11277–95-10. A portion of this study was presented at the meeting of the British Pharmacological Society, December 10–12 1997, Harrogate, UK and appeared in abstract form in Br J Clin Pharmacol45:P519–P520 (1998).

  • Abbreviations:
    CLint
    intrinsic clearance
    CYP
    cytochrome P-450
    DEM
    dextromethorphan
    DOR
    dextrorphan
    MEM
    methoxymorphinan
    CLmax
    clearance at maximal activation
    Css
    steady-state plasma concentration
    SRW
    standard rat weight of 250 g
    • Received October 28, 1998.
    • Accepted February 15, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 290 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 290, Issue 1
1 Jul 1999
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Research ArticleArticle

Sigmoidal Kinetics of CYP3A Substrates: An Approach for Scaling Dextromethorphan Metabolism in Hepatic Microsomes and Isolated Hepatocytes to Predict In Vivo Clearance in Rat

Lynn E. Witherow and J. Brian Houston
Journal of Pharmacology and Experimental Therapeutics July 1, 1999, 290 (1) 58-65;

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Research ArticleArticle

Sigmoidal Kinetics of CYP3A Substrates: An Approach for Scaling Dextromethorphan Metabolism in Hepatic Microsomes and Isolated Hepatocytes to Predict In Vivo Clearance in Rat

Lynn E. Witherow and J. Brian Houston
Journal of Pharmacology and Experimental Therapeutics July 1, 1999, 290 (1) 58-65;
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