Chapter 32 - CYP Inhibition Methods

Abstract

Cytochrome P450 (CYP) inhibition is a major cause of drug–drug interactions (DDI). Because DDI can lead to toxicity, considerable attention is given to methods for measuring CYP inhibition. Most pharmaceutical companies have implemented CYP inhibition testing during the discovery process. Measurement of CYP inhibition during discovery provides early warning of potential safety issues. It is used with other data to select leads and helps develop structure–CYP inhibition relationships that are used by medicinal chemists to overcome CYP inhibition by structural modification. Approaches have been developed to predict in vivo DDI using in vitro data. Two software companies offer tools for predicting CYP inhibition. CYP inhibition methodology is an active area of research, and several methods have been reported. The greatest current use of in silico CYP inhibition methods appears to be screening compound libraries for compounds with potential problems and guidance of medicinal chemists during the structure optimization stage on modifications that may yield reduced CYP inhibition. Computational docking to individual CYP isozyme structures using information from contemporary reports should enhance the in silico predictions of the future.