Drug metabolism and metabolite safety assessment in drug discovery and development

ABSTRACT

Introduction: 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 In the past several decades, a number of drugs have been withdrawn from the market due to safety issues caused by metabolites, especially reactive metabolites (RMs).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
• metabolite identification
• drug–drug interactions
• idiosyncratic adverse drug reactions
• reactive metabolites
• safety assessment
• species difference

Article highlights

• Drug metabolism affects the bioavailability of a drug and duration of effect, and in turn the pharmacological and toxicological effects. In recent decades, drug metabolism has become an indispensable approach for lead optimization to reduce drug attrition.

• When assessing the safety of a drug and its metabolites, several factors need to be taken into consideration, such as dose, species differences, in vitro and in vivo correlations, especially in vivo animal toxicological findings, and drug/metabolite accumulation not only in plasma, but also in tissues.

• Formation of reactive metabolites (RMs) is an unwanted characteristic for a drug candidate, and in some circumstances RMs are responsible for idiosyncratic adverse drug reactions (IADRs).

• The interplay between RMs and the risk of IADRs is complex and difficult to establish. Although RMs-positive is considered a liability during the preclinical evaluation, RMs do not always indicate that there is an increased likelihood of the occurrence of IADRs in the clinic. Dose and multiple metabolic pathways can also significantly affect the occurrence of IADRs.

• Drugs with low bioactivation potential are inherently much safer. Through the avoidance of structural alerts, the risk of IADRs is reduced or eliminated; however, this approach may overexaggerate the role of RMs in IADRs in some circumstances.

This box summarizes key points contained in the article.

Acknowledgments

We are very grateful for Dr. Matthew Miller (Eternity Bioscience, Inc.) for proofreading this manuscript with valuable comments.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

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Funding

This paper is not funded.