Pharmacotherapy is based on the interplay of pharmacokinetics and pharmacodynamics, which allows scientists to understand the effect drugs have on the human body and helps researchers develop drugs that are safe and effective. These two concepts explain how the body impacts drugs (pharmacokinetics) and how those drugs can then impact the body (pharmacodynamics).
The nuclear receptor superfamily is a group of intracellular transcription factors that directly regulate gene expression in response to lipophilic molecules. These receptors are found in metazoan organisms such as nematodes, insects, and vertebrates. Nuclear receptors affect a wide variety of physiologic functions including development, reproduction, and metabolism and are associated with diseases such as Alzheimer’s, cancer, and diabetes.
INDIGO Biosciences cell-based reporter assays have been used in environmental research on water for years due to their ease of use. Our CSO Jack Vanden Heuvel has even done his own research in this field utilizing INDIGO kits. (Take a look at the posters “Environmental and human health impacts of spreading oil and gas wastewater on roads” and “Detection and removal of biologically active organic micropollutants from hospital wastewater.”) Using in vitro receptor transactivation assays like those produced by INDIGO Biosciences is a crucial step to improve monitoring of our water systems and decrease the risk posed by complex mixtures of chemicals in the environment. Reporter assays can detect the cumulative toxicity posed by mixtures of known and unknown chemicals found in a sample. Cell-based nuclear receptor specific reporter assays such as INDIGO’s estrogen receptor assays, androgen receptor assays, and thyroid receptor assays can screen for endocrine-like activity in water samples that can cause adverse health effects to humans and the environment.
Endocrine disrupting chemicals (EDCs) are a class of pollutants that has garnered a lot of attention. These are specific chemicals that disrupt or interfere with elements of endocrine signaling, a critical system that controls metabolism, growth, tissue, reproduction, mood, and other factors and functions in the human body. Depending on the type and outcome, EDCs can impact puberty, immune function, stress, weight, bone health, and more. Some common examples of sources of EDCs are:
Environmental toxicology is a multidisciplinary field of science concerned with the study of the harmful effects of various chemical, biological, and physical agents on living organisms. Environmental toxicologists study the effects of toxicants at various concentrations in labs and try to understand the potential for the bioaccumulation in food webs, including our own food supply. Harmful effects of chemicals like DDT and pollutants, insecticides, pesticides, and fertilizers have been found to affect organisms and their communities by reducing species diversity and abundance. These changes in population dynamics then affect the ecosystem by reducing its productivity and stability.
The assessment of a drug candidate’s cross-activity with human xenobiotic-sensing receptors provides important early indications of that drug’s potential for downstream drug-drug interactions or other toxicology concerns. Prior to moving into human trials, preclinical studies utilize animals as human surrogates to assess a drug’s pharmacokinetic and toxicologic profiles. A wide range of animal models are used in preclinical studies for drug discovery including mice, rats, dogs, zebrafish, rabbits, and non-human primates. In research, these animals are used because they are orthologs. Orthologs are animals of different species that share genes that evolved from a common ancestor and have retained a similar function to those genes in humans.
Many compounds in the drug discovery process will be impacted by drug-nutrient interactions (DNI) and because of this, have the possibility to fail in clinical trials or have subsequent pharmacokinetic consequences. Xenobiotic nuclear receptors are known to play a significant role in DNI’s. Understanding what DNI’s are and knowing if they will modulate a drugs bioavailability can be important to success in clinical trials, as well as preventing potentially fatal drug-food and drug-herb interactions.
The microbiome or microbiota are the terms used for the microbes that live on and inside the human body. Trillions of microorganisms make up the microbiome including bacteria, fungi, parasites, and viruses. It is estimated that there are more microbial cells than human cells in the body and the majority of these microbes reside in the gut. There is a growing amount of research that has recently changed our understanding of the microbiome from being just a collection of symbiotic organisms to actively participating in a bidirectional communication system called the gut-brain axis.
The endocannabinoid system (ECS) is a complex cell-signaling system made up of cannabinoid receptors and the endogenous lipids called endocannabinoids that bind to them. This system was identified in the early 1990s with the cloning of the G-protein coupled receptors (GPCR) Cannabinoid Type 1 Receptor (CB1R) and Cannabinoid Type 2 Receptor (CB2R), as well as the identification of endogenous cannabinoids anandamide (AEA) and 2-arachidonoyl glycerol (2-AG).
Traditional toxicology practices focus on characterizing a single compound in regulatory GLP toxicology studies over a long period of time directly prior to clinical phase 1 trials. By this time, large amounts of time and resources have been invested into finding a single drug candidate. If a liability is found, researchers are left deciding if the benefits outweigh potential liabilities or if they need to start over, having spent time and resources on that single candidate. With late-stage failures due to toxicity continuing to be a primary cause for compound attrition, incorporating predictive in vitro testing into the discovery process is essential for those working in drug discovery.
