Metabolomics, the study of small-molecule metabolites, is becoming increasingly important in understanding the mechanisms behind cellular activity and disease. Historically, metabolites have been either supplemented or eliminated from growth media and diets to modulate cellular activity and affect phenotype. However, with the advancements in technology and the rise of the multi-omics era, the value of metabolomics has been redefined from a simple biomarker identification tool to a technology for discovering active drivers of biological processes.
The Metabolome Regulates Other Omics
The metabolome, the collection of small-molecule chemical entities involved in metabolism, has traditionally been studied to identify biomarkers in the diagnosis and prediction of disease. However, it is now clear that the metabolome affects cellular physiology by modulating other omics levels, including the genome, epigenome, transcriptome, and proteome. This concept of utilizing metabolomics to perform activity screens to identify biologically active metabolites, referred to as activity metabolomics, is already having a broad impact on biology.1
How Does the Metabolome Regulate Physiology?
Unlike proteins or genes, endogenous metabolites are readily amenable to biological testing and clinical applications. Metabolomics is used to identify the set of metabolites that are associated with physiological conditions or aberrant processes. The main focus of the field has been on using this information to identify biomarkers and active or dysregulated pathways. However, the perception of metabolites mainly as downstream products (inactive metabolites) has minimized the awareness of their far-reaching regulatory activity. In fact, the metabolome interacts with and actively modulates all other omics levels. Through this interaction, metabolites also serve as direct modulators of biological processes and phenotypes (active metabolites).
Activity Metabolomics Application to Drug Discovery
One application of activity metabolomics is in drug discovery and development. Drug metabolism is the chemical alteration of a drug by the body, playing an essential role in drug discovery and safety. When the body metabolizes drugs, the metabolites that result from their metabolism may be active or inactive. Inactive and active metabolites are important pharmacology concepts pertaining to how drugs interact with the body. Understanding the different types of metabolites and how they are formed can provide insight into how drugs produce their desired pharmacological effects and how they are eliminated from the body.
What are Inactive Metabolites?
Inactive metabolites are chemical compounds formed when a drug is metabolized by the body but do not have any significant biological effects. These compounds are usually less potent than the original drug as they have been broken down and may have lost some of their original structure. These compounds are eliminated from the body through the urine or feces and typically do not contribute to the overall pharmacological effects of a drug. In most cases, drugs are mainly metabolized into inactive compounds. For instance, when the body metabolizes paracetamol (acetaminophen), it is converted into several inactive metabolites that are excreted via urine.2
What are Active Metabolites?
Unlike inactive metabolites, active metabolites can produce significant biological effects in the body. They can interact with the body’s receptors and even be more potent than the original drug. Active metabolites can be formed through various metabolic processes, such as oxidation, reduction, and hydrolysis. An example of a drug that produces active metabolites is codeine. When the body metabolizes codeine, it is converted into morphine, a potent opioid analgesic.3
What are Pro-drugs?
Another important concept related to inactive and active metabolites is the concept of “pro-drugs.” Pro-drugs are inactive compounds that are converted into active drugs by the body. An example of a pro-drug is valacyclovir, an antiviral drug used to treat herpes. The body metabolizes Valacyclovir into acyclovir, the active form of the drug.4
Pharmacological Effects of Active Metabolites
The formation of active metabolites can have both positive and negative effects. They can increase the drug’s effectiveness, as in the case of codeine’s conversion to morphine. Conversely, they can lead to unwanted side effects, as some active metabolites may have different or even opposing effects to the original drug. The formation of active metabolites can also lead to drug-drug interactions. Some active metabolites may inhibit or induce the enzymes involved in their metabolism, or the metabolism of other drugs, leading to changes in the drug’s efficacy and safety. Therefore, the formation of active metabolites should be carefully considered during the drug development process.
Metabolon Can Detect Inactive and Active Metabolites
Understanding the different types of metabolites and how they are formed is crucial in drug development. Therefore, the formation of inactive and active metabolites should be carefully considered during the drug development process to ensure the safety and efficacy of the drug. The Metabolon Global Discovery Panel or Targeted Panels can be used to investigate the metabolism of pharmacological drugs or identify specific changes in the metabolome that can be related to the effects induced by these drugs. Metabolon can help you identify active and inactive metabolites to improve the safety and efficacy of drugs, improving the odds of successful drug development and, in the future, better clinical trial outcomes.
- Rinschen MM, Ivanisevic J, Giera M, Siuzdak G. Identification of bioactive metabolites using activity metabolomics. Nat Rev Mol Cell Biol. 2019;20(6):353-367. doi:10.1038/s41580-019-0108-4
- Mazaleuskaya LL, Sangkuhl K, Thorn CF, FitzGerald GA, Altman RB, Klein TE. PharmGKB summary: pathways of acetaminophen metabolism at the therapeutic versus toxic doses. Pharmacogenet Genomics. Aug 2015;25(8):416-26. doi:10.1097/FPC.0000000000000150
- Gourlay GK, Mitchell JRA. Codeine. In: Aitkenhead AR, Smith G, eds. Textbook of Anaesthesia. 6th ed.
- Tyring SK, Baker D, Snowden W. Valacyclovir for herpes simplex virus infection: long-term safety and sustained efficacy after 20 years’ experience with acyclovir. J Infect Dis. Oct 15 2002;186 Suppl 1:S40-6. doi:10.1086/342966