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Development and application of an integrated drug‐drug interaction database focused on drug‐metabolizing P450 enzymes

Drug‐drug interactions (DDIs) caused by direct chemical inhibition of key drug‐metabolizing cytochrome P450 enzymes (CYPs) by a co‐administered drug have been well documented and well understood. However, many other well‐documented DDIs can not be so readily explained. Recent investigations into drug and other xenobiotic‐mediated expression changes of CYP genes have broadened our understanding of drug metabolism and DDI. In order to gain additional information on DDI, we have integrated existing information on drugs that are substrates, inhibitors, or inducers of important drug‐metabolizing CYPs with new data on drug‐mediated expression changes of the same set of CYPs from DrugMatrix®, a large‐scale microarray gene expression database of drug‐treated rat tissues. The integrated information has been organized into a drug‐cytochrome P450 matrix which facilitates comparative analysis of drugs that are P450 substrates against drugs that are P450 inhibitors or inducers/suppressors of CYP gene expression. When examined at the gene expression level, 119 currently marketed drugs from 265 studied were CYP inducers and 83 were suppressors. Information in this drug‐drug interaction database allows the user to consider drug‐mediated CYP‐suppression as a mechanism for previously well documented but not well understood DDIs. The value of this new information will be illustrated by a number of examples.