Abstract
The relationship between time-dependent inactivation (TDI) and IC50 is examined using a consolidated method for evaluating CYP450 inhibition during drug discovery. An IC50 fold-shift of >1.5 indicated significant TDI potency. Further, the "shifted IC50" could be used to estimate, the K(I) and TDI potency ratio k(inact)/K(I) to within 2-fold in most cases.
MeSH terms
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Aryl Hydrocarbon Hydroxylases / antagonists & inhibitors*
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Cytochrome P-450 CYP2C9
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Cytochrome P-450 CYP2D6 Inhibitors*
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Cytochrome P-450 CYP3A
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Cytochrome P-450 CYP3A Inhibitors*
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Enzyme Inhibitors / administration & dosage
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Enzyme Inhibitors / pharmacology*
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Humans
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Inhibitory Concentration 50
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Microsomes, Liver / drug effects
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Microsomes, Liver / enzymology
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Models, Biological
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Time Factors
Substances
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Cytochrome P-450 CYP2D6 Inhibitors
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Cytochrome P-450 CYP3A Inhibitors
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Enzyme Inhibitors
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CYP2C9 protein, human
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Cytochrome P-450 CYP2C9
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Aryl Hydrocarbon Hydroxylases
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Cytochrome P-450 CYP3A
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CYP3A4 protein, human