Editorial

The topic of mechanism-based inactivation (MBI) of cytochrome P450 enzymes has been recently emerging as one of ever increasing importance. While our knowledge of some of the biochemistry and chemistry of the phenomenon of MBI of P450 enzymes has been with us for over three decades, the ramifications of MBI in drug discovery and clinical pharmacokinetics have been appreciated only more recently. While drug label warnings and contraindications due to P450 based drug-drug interactions (DDI) are numerous, the only drug known to be removed from the market due to an unfavorable drug-drug interaction profile (as a perpetrator of DDIs) was in fact a mechanism-based inactivator (mibefradil). Work done by Hall and co-workers over the past several years (Mayhew, et al., 2000; Wang, et al., 2004), as well as that of other eminent investigators has elevated the science such that we can now relate in vitro MBI to in vivo DDI. The importance of MBI in the development of new drugs has not gone unnoticed by government regulatory authorities. The FDA has included an assessment of MBI as an essential component to drug development in its recently released draft guidance document (FDA, 2006). Because of the importance of this topic, Current Drug Metabolism is publishing two back-to-back comprehensive reviews on MBI that were written by colleagues of mine at the research laboratories of Pfizer, Inc. In the first, the types of structures that can cause MBI of cytochrome P450 enzymes are described, as a useful reference for those involved in the chemical design of new drugs. The implications of MBI regarding DDI and pharmacokinetics are alluded to as a form of an introduction to the topic. In the second, the details are laid out regarding the mathematics behind how in vitro MBI data can be used in the development of drugs, for the prediction of DDI, and the design of clinical study strategies. We hope that the readers of Current Drug Metabolism find these two articles to be of value to their research efforts aimed toward the discovery and development of safe and effective new agents that will lack the property of causing DDI via mechanism-based inactivation of P450 enzymes. FDA (2006) Guidance for Industry. Drug Interaction Studies - Study Design, Data Analysis, and Implications for Dosing and Labeling http://www.fda.gov/cber/gdlns/interactstud.htm (accessed, March 27, 2007). Mayhew BS, Jones DR, Hall SD. (2000) An in vitro model for predicting in vivo inhibition of cytochrome P450 3A4 by metabolic intermediate complex formation. Drug Metab Dispos 28: 1031-1037. Wang YH, Jones DR, Hall SD. (2004) Prediction of cytochrome P450 3A inhibition by verapamil enantiomers and their metabolites. Drug Metab Dispos 32: 259-266.