Unit

UNIT 7.14 Assessment of the Time-Dependent Inhibition (TDI) Potential of Test Compounds with Human Liver Microsomes by IC50 Shift Method Using a Nondilution Approach

  1. Lian de Ron,
  2. Ganesh Rajaraman

Published Online: 1 SEP 2012

DOI: 10.1002/0471141755.ph0714s58

Current Protocols in Pharmacology

Current Protocols in Pharmacology

How to Cite

de Ron, L. and Rajaraman, G. 2012. Assessment of the Time-Dependent Inhibition (TDI) Potential of Test Compounds with Human Liver Microsomes by IC50 Shift Method Using a Nondilution Approach. Current Protocols in Pharmacology. 58:7.14:7.14.1–7.14.13.

Author Information

  1. NoAb BioDiscoveries, Mississauga, Ontario, Canada

Publication History

  1. Published Online: 1 SEP 2012

Abstract

Time-dependent inhibition (TDI) of hepatic cytochrome P450 (CYP) enzymes is increasingly implicated in the majority of clinically relevant drug-drug interactions (DDIs). A time-dependent inhibitor or its reactive metabolite irreversibly inactivates CYP enzymes, thereby inhibiting the metabolism of other drugs. As the majority of marketed drugs are metabolized by CYP enzymes, their inhibition has important clinical consequences, such as in decreasing the metabolic clearance of a co-administered drug (victim drug). This could be life threatening, as such an effect narrows the therapeutic index for drugs such as warfarin and other potentially toxic agents. Therefore, it is essential to examine new chemical entities for their potential to cause TDI to minimize adverse drug reactions during human studies and use. This unit presents an in vitro procedure utilizing a nondilution method in human liver microsomes for determining the TDI potential of test compounds. Curr. Protoc. Pharmacol. 58:7.14.1-7.14.13. © 2012 by John Wiley & Sons, Inc.

Keywords:

  • time-dependent inhibition;
  • mechanism-based inhibition;
  • human liver microsomes;
  • cytochrome P450