NonMichaelisMenten Kinetics
The observation of atypical enzyme kinetics, particularly involving CYP, has become relatively common. Since predictions of in vivo clearances are based on kinetic parameters observed during in vitro experiments, misidentification of the drug kinetic profile can lead to inaccurate predictions of intrinsic clearance.34
The atypical kinetic profiles include autoactivation (sigmoidal kinetics or homotropic cooperativity), substrate inhibition, heteroactivation (heterotropic cooperativity), partial inhibition, and substrate-dependent inhibition (see Hutzler and Tracy35 for a review of enzymes exhibiting atypical kinetics).
Among these atypical kinetic profiles, autoactivation kinetics have been more and more observed over the past few years, particularly for CYP3A and 2C9. In this case, the v versus S plot yields a sigmoidal curve, attributed to more than one substrate molecule simultaneously binding to the enzyme and stimulating the activity. To prevent the underestimation of the CLint in case of autoactivation, Houston etal.36 suggested the use of the CLmax, describing the steepest part of the v versus S curve and being visualized as the maximum point on a plot of v/S versus S. However this type of model36,37 remains by far too complex to be integrated in early drug discovery.
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