Study your rats so the results don't bite
identical they can still develop distinct metabolic profiles that
could skew drug toxicity and metabolism studies.
Mammals house large microfloral populations (around 1013 microbes) in the gastrointestinal (GI) tract that play a key role in intestinal development, health, immune response as well as food and drug metabolism. The latest research, published as an early access article in the journal Chemical Research in Toxicology by researchers from Pfizer and Charles River Laboratories, shows how sensitive these phenotypes are and highlights the need to monitor the metabolic profiles of all laboratory animals used in drug screening experiments. "Changes in the microflaura population may alter the types of reactions that can be performed [in the GI tract], modify the metabolite profile and potentially limit or enhance the bioavailability of various ingested compounds," write the researchers. Because the bacterial populations can play such an important role in immune response and drug metabolism, it is key that any inter-animal variation is detected before they are used in drug safety assessment studies. The microflora populations are acquired shortly after birth and they are very sensitive to infection, stress, hygiene and the administration of antibiotics. To try to avoid microflora population variations and ensure lab rats stay healthy and germfree, 'altered Schaedler flora' (ASF) rats with limited gut floral populations have been developed with standardised microbiota populations. However, the researchers noticed that two very distinct phenotypes of genetically identical Sprague-Dawley ASF rats had originated from within a Charles River Laboratories facility by examining their urinary metabolic profiles using NMR techniques (nuclear magnetic resonance). They showed that one phenotype, named HIP, could be characterised by high hippurate and low chlorogenic acid metabolite levels, while the other, designated CA, exhibited the reverse ratio. The researchers showed that the CA rats originating from a colony initiated in 2002 could be converted, albeit at a variable rate, to the HIP phenotyping by exposure to either HIP rats or their bedding. The authors note that while it would have been interesting "to further explore the differences between the HIP and CA rats, especially with respect to how their differences might affect drug metabolism, the CA rats are no longer available... [as they] have now reverted to the HIP phenotype". Changes to how laboratory animals metabolise drugs could lead to the generation of spurious results during drug toxicity studies that could irreparably damage applications for Phase I trials. "Screening populations for phenotypic metabolic differences should be considered as these differences may influence the results of research investigations, especially safety assessment studies," write the authors.