Assessing Drug Toxicity in Pre-Clinical In Vivo Studies: Considering the Microbiome
Before new medications can be approved for use, they must be evaluated for potential toxicity. Traditional studies focus on how drugs move and behave once inside the body, called pharmacokinetics, but new insights suggest the process may be more complex than was previously thought. Emerging research into the human microbiome shows that organisms which are living in the human gut can potentially have a profound effect on exactly how drugs are metabolized and absorbed, ultimately affecting how individuals respond to treatments.
Tiny Microbes Can Have Big Effects
The microbiota in the human gut works constantly to break down food compounds, produce beneficial metabolites and train the immune system. More than 1000 different species of microorganism reside in the gut alone, outnumbering human cells and weighting up to 2kg.
Beyond its role for food absorption, this dense population also plays a role in drug metabolism as it breaks down pharmaceutical compounds in the digestive tract. When microbes are involved in the metabolism of drugs, it can result in the production of metabolites of varying toxicities. Therefore the microbiome has the potential to change how patients react to medications.
The health and balance of the human microbiome is influenced by many factors, including:
- Method of birth
- Antibiotic exposure in early life
- Recent exposure to antibiotics and other drugs
- Composition of diet
- Stress levels
Fluctuations in microbiome diversity occur throughout life. Sudden interruptions in balance, such as courses of broad-spectrum antibiotics, can create a dysbiotic state in which digestive and immune function is altered. This changes the way individuals react to and handle pathogens and may also increase the risk of disease, such as diabetes and cardiovascular diseases. Research indicate that drug developers must take these fluctuations and disturbances into consideration when testing physiological drug properties such as absorption, distribution, metabolism, and excretion (ADME testing) for new pharmaceutical preparations.
ADME Testing for Pharmacokinetic Effects
An ADME test is the standard model for testing pharmacokinetics and monitors four different areas of drug movement and action:
- Absorption – General bioavailability based on how much of a substance is absorbed and how quickly it enters circulation
- Distribution – Where a drug goes in the body and how long it takes to get to its intended target
- Metabolism – The speed at which the body breaks down a substance, what methods are used for metabolism and whether the resulting byproducts are active or toxic
- Elimination – How long it takes for a drug to pass out of the body and the pathways used to get rid of it
In vivo ADME studies are most often performed on lab animals, including mice, to determine the overall potency and efficiency of a drug. Taking the microbiota into consideration adds another layer of intricacy to these tests. Instead of looking at a standard model as a representation of the general human population, various combinations of gut microbes are introduced and assessed.
Testing Toxicity with Microbes in Mind
Looking at different human microbiota populations in ADME studies can help determine whether particular strains or groups of strains can affect the potency, stability and toxicity of new drugs in different populations. Dysbiosis in the gut can cause measurable changes in the level of enzymes involved in drug metabolism, and these changes may be profound enough to cause serious side effects in subgroups of patients. Some patients may experience little or no benefit from a drug used with great success in the majority of the population (varying drug response).
Mice raised in sterile conditions without any microbes of their own, known as germ-free mice, are often used to test the influence of gut microbes on various conditions. By introducing human microbiota samples into germ-free specimens, researchers can determine correlations between microbial activities and the metabolism of pharmaceutical preparations. Specific effects in the realm of pharmacokinetics can be observed and recorded, thus providing information on how to treat patients based not only on their conditions but also on the variations of the populations in their guts.
Since the human microbiome can influence the way individuals metabolize, use and react to drugs, it’s important for pharmaceutical companies to consider ADME testing that consider the gut microbiome. However the high complexity, variability and instability of the gut microbiome, as well as the variation between the microbiome between host species, complicate the efforts and optimal approaches remain to lacking.
Early attempts are undertaken where doctors consider the microbiome profile of patients as part of their examinations, aiming for a more personalized approach to treatment and diagnosis. By working together with microbes in mind, drug companies and physicians may be able to create more personalized, targeted and effective pharmaceutical therapies for all patients. Ideally, drug recommendations and dosages should be tailored to the individual based on factors including the specific microbiota profile.
- >> Effect of Intestinal Flora on Protein Expression of Drug-Metabolizing Enzymes and Transporters in the Liver and Kidney of Germ-Free and Antibiotics-Treated Mice. Kuno T, et. al. 2016. PMID: 27376980 (https://www.ncbi.nlm.nih.gov/pubmed/27376980)
- >> Gut Microbiome Function Predicts Response to Anti-integrin Biologic Therapy in Inflammatory Bowel Diseases. Ananthakrishnan et al. 2017. OMID: 28494241 (https://www.ncbi.nlm.nih.gov/pubmed/28494241)
- >> Drug Metabolism by the Host and Gut Microbiota: A Partnership or Rivalry? Swanson, 2015. PMID: 26261284 (https://www.ncbi.nlm.nih.gov/pubmed/27376980)
- >> Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Gopalakrishnan et al., 2018. PMID: 29097493. (https://www.ncbi.nlm.nih.gov/pubmed/29097493)