Lessons learnt from comparative species’ studies

Dear Reader,

When I am not performing my duties as an associate editor for this journal, my research area is veterinary pharmacology. During my early career, I conducted pharmacological research on a single companion animal species at a time; however, recently, I have come to appreciate the value of comparative species research as it highlights crucial inter-species differences that require consideration when formulating research plans and interpreting results.

This idea became apparent when my research group commenced studies into the pharmacokinetic profiles of first-line veterinary medicines used to treat the iconic Australian species, the koala (Phascolarctos cinereus). The koala is considered a highly valuable animal in Australia and unfortunately they are at risk to injury by car strikes, feral dog attacks and burns from bushfires for which they require medical treatment. Prior to 2010, the suggested dosages for medicines to treat koalas (the average weight of a mature koala is approximately 6–8 kg with the larger males around 10 kg) were generally extrapolated from dog and cat dosages. It was assumed that these dosages would have appropriate therapeutic outcomes. Our research demonstrated that dosages of some commonly registered veterinary medicines such as the antibacterial enrofloxacin and the non-steroidal anti-inflammatory drug meloxicam when administered orally, or subcutaneously, had lower bioavailability (i.e. the proportion of drug that finds its way into the circulation from the site of administration) compared to many other conventional domestic species (Griffith et al. 2010; Kimble et al. 2012a). As koalas are specialist folivores (their diet is almost exclusively Eucalyptus spp. leaves), the dietary roughage probably entraps drugs, thereby reducing oral absorption. However, we were curious about the lower subcutaneous bioavailability. We wondered whether the koalas were eliminating the drug faster than other species. Therefore, we performed an in vitro study to compare the rate of disappearance of meloxicam when incubated with hepatic microsomes (phase 1 metabolism enzymes) from koalas, possums, rats and dogs. This study demonstrated that the rate of disappearance of meloxicam was faster in the koala and the possums than in the rat or dog (Kimble et al. 2014). The results of this study provided evidence that possums and koalas, or Eucalypt spp. eating marsupials (animals with a pouch), metabolise meloxicam more rapidly than the eutherians (animals with placentas) and could be a factor to explain the lower subcutaneous and oral bioavailability in the koala. Other species differences we have found included when conducting liquid chromatography analyses, that the koala plasma had many more visible and interfering chromatographic peaks than other species, which we hypothesized was dietary related (Kimble et al. 2012b). We have also found that drug-plasma protein binding can be different for the koala. For example, fluconazole (an antifungal medicine) has greater in vitro plasma protein binding in koalas than in other species studied to date (Black et al. 2013). As it is the unbound drug that is therapeutically active, if there is a greater proportion of bound drug, dosages require modification to deliver the necessary therapeutic plasma concentration.

As our research expands to investigate the pharmacokinetic profiles of medicines in different species, we plan our studies by incorporating the lessons we have learnt from our previous studies. We commence formulating our research plan by initially consulting the existing species specific literature to uncover known species’ anatomical and physiological factors, natural dietary sources and composition, and behavioural idiosyncrasies, as any number of these factors may have a significant impact on the experimental design. We routinely check the drug free plasma for presence of endogenous chromatographic peaks and we incorporate determination of drug-plasma protein binding study as an essential component of any pharmacokinetic study.