Elsevier

Drug Discovery Today

Volume 11, Issues 3–4, February 2006, Pages 133-142
Drug Discovery Today

Review
Role of pharmacologically active metabolites in drug discovery and development

https://doi.org/10.1016/S1359-6446(05)03681-0Get rights and content

Pharmacologically active metabolites can contribute significantly to the overall therapeutic and adverse effects of drugs. Therefore, to fully understand the mechanism of action of drugs, it is important to recognize the role of active metabolites. Active metabolites can also be developed as drugs in their own right. Using illustrative examples, this paper discusses a variety of biotransformation reactions that produce active metabolites and their structure–activity relationships. The paper also describes the role and significance of active metabolites in drug discovery and development, various experimental observations that can be used as indicators of their presence, and methods that can be used to assess their biological activities and contribution to the overall therapeutic and adverse effects of drugs.

Section snippets

Biotransformation reactions leading to the formation of active metabolites

In general, biotransformation reactions are divided into two broad categories known as ‘phase I’ and ‘phase II’. Phase I reactions are functionalization reactions that introduce polar chemical moieties either by inserting new polar functional groups or by interchanging or unmasking existing functional groups via oxidation, reduction and hydrolytic reactions. Phase I reactions are mediated by enzymes such as cytochrome P450 (CYP), flavin-containing monooxygenase (FMO), esterases and amidases.

Structure–activity relationships

Although metabolites are chemically distinct from the parent drug, they have structural similarities to the parent molecules that might help them, to some degree, attain activities similar to the parent drug. As illustrated above, this is particularly true for those biotransformations that involve simple functionalization reactions, such as hydroxylation, O- or N-demethylation and dehydrogenation or heteroatom oxidation, as is the case with many CYP-mediated reactions. Examples, in addition to

Pharmacodynamic and pharmacokinetic aspects of active metabolites

Depending on the structural similarities and how well the bioactive conformation of the parent molecule is preserved or optimized during the biotransformation, metabolites can have a broad range of pharmacological activities. Consequently, potency, efficacy and the nature of the dose–response curve (flat, shallow or sharp) of an active metabolite relative to the parent are important determinants of the degree of its contribution to the overall therapeutic effect of the drug. For example, most

The significance of active metabolites in drug discovery and development

There are several reasons why it is important to be aware of the significance of pharmacologically active metabolites. Described below are some of the roles that active metabolite might play at the various stages of drug discovery (e.g. lead compound selection and optimization) and development.

Experimental indicators of the presence and involvement of active metabolites

There are several experimental observations that can be used as indicators of the presence and involvement of active metabolites. Some of them are discussed below.

Approaches used to assess pharmacological activity of metabolites

The presence and impact of active metabolites can be evaluated and confirmed using the following approaches.

Generation and structural characterization of active metabolites

Various biological or chemical methods can be utilized to generate active metabolites and to assess their in vitro and in vivo biological activity. Biological methods include incubation of the parent compound with various subcellular fractions (e.g. microsomes), individual recombinant drug-metabolizing enzymes, whole cells (e.g. hepatocytes) or tissue slices [8, 16]. In vivo samples such as bile, urine and plasma collected from experimental animals and humans following administration of the

Conclusions

Several drugs are biotransformed to pharmacologically active metabolites that can significantly contribute to the overall pharmacological or adverse effects of drugs. For the most part, the pharmacological actions attributed to active metabolites are similar to those of the parent. However, active metabolites could also mediate therapeutic effects that are synergistic or even the reverse of the pharmacological action of the parent drugs. They could also mediate pharmacological actions that are

Acknowledgements

The author gratefully acknowledges Dr David Rodrigues and Dr William Humphreys for their critical review of this manuscript.

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