An examination of IC50 and IC50-shift experiments in assessing time-dependent inhibition of CYP3A4, CYP2D6 and CYP2C9 in human liver microsomes

Loren M Berry; Zhiyang Zhao

doi:10.2174/187231208783478407

An examination of IC50 and IC50-shift experiments in assessing time-dependent inhibition of CYP3A4, CYP2D6 and CYP2C9 in human liver microsomes

Drug Metab Lett. 2008 Jan;2(1):51-9. doi: 10.2174/187231208783478407.

Authors

Loren M Berry¹, Zhiyang Zhao

Affiliation

¹ Pharmacokinetics and Drug Metabolism, Amgen, Inc., 1 Kendal Sq., Cambridge, MA 02139, USA. loren.berry@amgen.com

PMID: 19356071
DOI: 10.2174/187231208783478407

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

Aryl Hydrocarbon Hydroxylases / antagonists & inhibitors*
Cytochrome P-450 CYP2C9
Cytochrome P-450 CYP2D6 Inhibitors*
Cytochrome P-450 CYP3A
Cytochrome P-450 CYP3A Inhibitors*
Enzyme Inhibitors / administration & dosage
Enzyme Inhibitors / pharmacology*
Humans
Inhibitory Concentration 50
Microsomes, Liver / drug effects
Microsomes, Liver / enzymology
Models, Biological
Time Factors

Substances

Cytochrome P-450 CYP2D6 Inhibitors
Cytochrome P-450 CYP3A Inhibitors
Enzyme Inhibitors
CYP2C9 protein, human
Cytochrome P-450 CYP2C9
Aryl Hydrocarbon Hydroxylases
Cytochrome P-450 CYP3A
CYP3A4 protein, human