Drug metabolism and metabolite safety assessment in drug discovery and development

Expert Opinion on Drug Metabolism & Toxicology
Chunyong He, Hong Wan

Abstract

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 In the past several decades, a number of drugs have been withdrawn from the market due to safety issues caused by metabolites, especially reactive metabolites (RMs).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 be...Continue Reading

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Citations

Jul 14, 2020·Biomedical Chromatography : BMC·Yiqian HuangXiaosong Huang
Jun 20, 2020·Biomedical Chromatography : BMC·Ying LiuJianshe Chen
Jan 21, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Guiqiu ZhangChen Ma
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Sep 16, 2020·Chemical Reviews·Kylie A Agnew-Francis, Craig M Williams

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