In silico prediction models of the induction of drug-metabolizing enzymes for drug discovery

Abstract

Drug metabolism in the liver is a major factor affecting pharmacokinetics of drugs, and cytochrome P450s (P450s) are major enzymes responsible for it. Since drug-drug interactions (DDIs) can affect the pharmacokinetics of concomitantly administrated drugs, it may limit the drug therapy such as dose adjustment and contraindications for co-administration and lead to dose adjustment and contraindications for co-administration. DDI is thus one of the risk factors to be reduced in the lead-optimization stage. Therefore, it is important to estimate DDI risk in the early drug discovery stage and develop candidates with low DDI risk. P450 induction is one of the important mechanisms causing DDIs and the activation of nuclear receptors is involved in this phenomenon. In this manuscript, the mechanism and evaluation methods of P450 induction are briefly reviewed, and then the new in silico methods for the prediction of P450 induction, which have been recently established by us, and its application to drug development are introduced.