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Review ArticleReview

In Vitro-In Vivo Scaling of CYP Kinetic Data Not Consistent with the Classical Michaelis-Menten Model

J. Brian Houston and Kathryn E. Kenworthy
Drug Metabolism and Disposition March 2000, 28 (3) 246-254;
J. Brian Houston
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Kathryn E. Kenworthy
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Abstract

Strategies for the prediction of in vivo drug clearance from in vitro drug metabolite kinetic data are well established for the rat. In this animal species, metabolism rate-substrate concentration relationships can commonly be described by the classic hyperbola consistent with the Michaelis-Menten model and simple scaling of the parameter intrinsic clearance (CLint − the ratio of Vmax to Km) is particularly valuable. The in vitro scaling of kinetic data from human tissue is more complex, particularly as many substrates for cytochrome P450 (CYP) 3A4, the dominant human CYP, show nonhyperbolic metabolism rate-substrate concentration curves. This review critically examines these types of data, which require the adoption of an enzyme model with multiple sites showing cooperative binding for the drug substrate, and considers the constraints this kinetic behavior places on the prediction of in vivo pharmacokinetic characteristics, such as metabolic stability and inhibitory drug interaction potential. The cases of autoactivation and autoinhibition are discussed; the former results in an initial lag in the rate-substrate concentration profile to generate a sigmoidal curve whereas the latter is characterized by a convex curve as Vmax is not maintained at high substrate concentrations. When positive cooperativity occurs, we suggest the use of CLmax, the maximal clearance resulting from autoactivation, as a substitute forCLint. The impact of heteroactivation on this approach is also of importance. In the case of negative cooperativity, care in using theVmax/Km approach toCLint determination must be taken. Examples of substrates displaying each type of kinetic behavior are discussed for various recombinant CYP enzymes, and possible artifactual sources of atypical rate-concentration curves are outlined. Finally, the consequences of ignoring atypical Michaelis-Menten kinetic relationships are examined, and the inconsistencies reported for both different substrates and sources of recombinant CYP3A noted.

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}fs1.pa.man.ac.uk

  • ↵1 Present address: Department of Drug Metabolism and Pharmacokinetics, SmithKline Beecham Pharmaceuticals, The Frythe, Welwyn, Herts AL6 9AR, UK.

  • K.E.K. was supported by a SmithKline Beecham studentship.

  • Abbreviations used are::
    CYP
    cytochrome P450
    ANF
    α-naphthoflavone
    β-LM
    β-lymphoblastoid
    CLint
    intrinsic clearance
    CLmax
    maximal clearance due to autoactivation
    Ksi
    inhibition constant for substrate inhibition
    n
    the Hill coefficient
    S50
    substrate concentration resulting in 50% of Vmax
    Smax
    substrate concentration resulting in maximal clearance due to autoactivation
    • Received August 11, 1999.
    • Accepted November 2, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 28 (3)
Drug Metabolism and Disposition
Vol. 28, Issue 3
1 Mar 2000
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Review ArticleReview

In Vitro-In Vivo Scaling of CYP Kinetic Data Not Consistent with the Classical Michaelis-Menten Model

J. Brian Houston and Kathryn E. Kenworthy
Drug Metabolism and Disposition March 1, 2000, 28 (3) 246-254;

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Review ArticleReview

In Vitro-In Vivo Scaling of CYP Kinetic Data Not Consistent with the Classical Michaelis-Menten Model

J. Brian Houston and Kathryn E. Kenworthy
Drug Metabolism and Disposition March 1, 2000, 28 (3) 246-254;
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  • Article
    • Abstract
    • Use of the Michaelis-Menten Model for Describing Drug Metabolite Kinetics In Vitro
    • Deviations from the Michaelis-Menten Relationship for CYP
    • Are There In Vivo Consequences?
    • Calculation of Maximal Clearance due to Autoactivation (CLmax)
    • Consequences of Ignoring Nonhyperbolic Kinetic Behavior
    • Inconsistencies between Substrates and Sources of Recombinant CYP3A4
    • Conclusion
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    • Derivation of Clmax
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