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Vol. 28, Issue 3, 246-254, March 2000
School of Pharmacy and Pharmaceutical Sciences, University of
Manchester, Manchester, United Kingdom
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 for
CLint. The impact of heteroactivation on this approach is also of importance. In the case of negative cooperativity, care in using the
Vmax/Km approach to
CLint 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.
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Y. Watanabe, M. Nakajima, and T. Yokoi Troglitazone Glucuronidation in Human Liver and Intestine Microsomes: High Catalytic Activity of UGT1A8 and UGT1A10 Drug Metab. Dispos., December 1, 2002; 30(12): 1462 - 1469. [Abstract] [Full Text] [PDF]
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A. Galetin, S. E. Clarke, and J. B. Houston Quinidine and Haloperidol as Modifiers of CYP3A4 Activity: Multisite Kinetic Model Approach Drug Metab. Dispos., December 1, 2002; 30(12): 1512 - 1522. [Abstract] [Full Text] [PDF]
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J. A. Williams, B. J. Ring, V. E. Cantrell, D. R. Jones, J. Eckstein, K. Ruterbories, M. A. Hamman, S. D. Hall, and S. A. Wrighton Comparative Metabolic Capabilities of CYP3A4, CYP3A5, and CYP3A7 Drug Metab. Dispos., August 1, 2002; 30(8): 883 - 891. [Abstract] [Full Text] [PDF]
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D. M. Stresser, S. D. Turner, A. P. Blanchard, V. P. Miller, and C. L. Crespi Cytochrome P450 Fluorometric Substrates: Identification of Isoform-Selective Probes for Rat CYP2D2 and Human CYP3A4. Drug Metab. Dispos., July 1, 2002; 30(7): 845 - 852. [Abstract] [Full Text] [PDF]
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S. Ekins, R. B. Kim, B. F. Leake, A. H. Dantzig, E. G. Schuetz, L.-B. Lan, K. Yasuda, R. L. Shepard, M. a Winter, J. D. Schuetz, et al. Application of Three-Dimensional Quantitative Structure-Activity Relationships of P-Glycoprotein Inhibitors and Substrates Mol. Pharmacol., May 1, 2002; 61(5): 974 - 981. [Abstract] [Full Text] [PDF]
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J. M. Hutzler and T. S. Tracy Atypical Kinetic Profiles in Drug Metabolism Reactions Drug Metab. Dispos., April 1, 2002; 30(4): 355 - 362. [Full Text] [PDF]
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T. S. Tracy, J. M. Hutzler, R. L. Haining, A. E. Rettie, M. A. Hummel, and L. J. Dickmann Polymorphic Variants (CYP2C9*3 and CYP2C9*5) and the F114L Active Site Mutation of CYP2C9: Effect on Atypical Kinetic Metabolism Profiles Drug Metab. Dispos., April 1, 2002; 30(4): 385 - 390. [Abstract] [Full Text] [PDF]
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K. E. Kenworthy, S. E. Clarke, J. Andrews, and J. B. Houston Multisite Kinetic Models for CYP3A4: Simultaneous Activation and Inhibition of Diazepam and Testosterone Metabolism Drug Metab. Dispos., December 1, 2001; 29(12): 1644 - 1651. [Abstract] [Full Text] [PDF]
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P. Lu, Y. Lin, A. D. Rodrigues, T. H. Rushmore, T. A. Baillie, and M. Shou Testosterone, 7-Benzyloxyquinoline, and 7-Benzyloxy-4-trifluoromethyl-coumarin Bind to Different Domains within the Active Site of Cytochrome P450 3A4 Drug Metab. Dispos., November 1, 2001; 29(11): 1473 - 1479. [Abstract] [Full Text] [PDF]
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Y. Oda and E. D. Kharasch Metabolism of Methadone and levo-alpha -Acetylmethadol (LAAM) by Human Intestinal Cytochrome P450 3A4 (CYP3A4): Potential Contribution of Intestinal Metabolism to Presystemic Clearance and Bioactivation J. Pharmacol. Exp. Ther., September 1, 2001; 298(3): 1021 - 1032. [Abstract] [Full Text] [PDF]
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R. E. White and P. Manitpisitkul Pharmacokinetic Theory of Cassette Dosing in Drug Discovery Screening Drug Metab. Dispos., July 1, 2001; 29(7): 957 - 966. [Abstract] [Full Text] [PDF]
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J. M. Hutzler, M. J. Hauer, and T. S. Tracy Dapsone Activation of CYP2C9-Mediated Metabolism: Evidence for Activation of Multiple Substrates and a Two-Site Model Drug Metab. Dispos., July 1, 2001; 29(7): 1029 - 1034. [Abstract] [Full Text] [PDF]
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K. Venkatakrishnan, L. L. von Moltke, and D. J. Greenblatt Application of the Relative Activity Factor Approach in Scaling from Heterologously Expressed Cytochromes P450 to Human Liver Microsomes: Studies on Amitriptyline as a Model Substrate J. Pharmacol. Exp. Ther., April 1, 2001; 297(1): 326 - 337. [Abstract] [Full Text]
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Y. Oda and E. D. Kharasch Metabolism of levo-{alpha}-Acetylmethadol (LAAM) by Human Liver Cytochrome P450: Involvement of CYP3A4 Characterized by Atypical Kinetics with Two Binding Sites J. Pharmacol. Exp. Ther., April 1, 2001; 297(1): 410 - 422. [Abstract] [Full Text]
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T. L. Domanski, C. Finta, J. R. Halpert, and P. G. Zaphiropoulos cDNA Cloning and Initial Characterization of CYP3A43, a Novel Human Cytochrome P450 Mol. Pharmacol., February 1, 2001; 59(2): 386 - 392. [Abstract] [Full Text]
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M. L. Schrag and L. C. Wienkers Triazolam Substrate Inhibition: Evidence of Competition for Heme-Bound Reactive Oxygen Within the CYP3A4 Active Site Drug Metab. Dispos., January 1, 2001; 29(1): 70 - 75. [Abstract] [Full Text]
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