Drug metabolism is one of the most important processes involving a drug after administration. Undesirable pharmacokinetic properties may lead to drug discontinuation. In the past several decades, a number of drugs have been withdrawn from the market due to safety issues caused by metabolites, especially reactive metabolites (RMs). Area covered: The focus of this review is on the role that drug metabolites play in drug discovery and developmental stages, with particular emphasis on metabolism-guided lead optimization, safety assessment of drug metabolites, drug-drug interaction potential of metabolites, and RMs safety assessment. In addition, species-related metabolic differences are briefly covered. Expert opinion: For the safety assessment of drug metabolites, a number of factors should be given full consideration, such as dose, in vitro and in vivo correlations, in vivo animal toxicological findings, and the accumulation of metabolites in plasma and/or tissues. Several factors, especially dose and multiple metabolic pathways, can significantly affect the occurrence of idiosyncratic adverse drug reactions (IADRs). Multiple assays should be used to assess RMs and thus avoid false-negative results. There is no clear interplay between the formation of RMs and the occurrence of IADRs. Avoidance of structural alerts and decreasing dose are the most effective strategies in reducing the risk of IADRs.
Keywords: Drug metabolism; drug–drug interactions; idiosyncratic adverse drug reactions; metabolite identification; reactive metabolites; safety assessment; species difference.