Investigation into gastrointestinal absorption of xenobiotics by the koala

A project undertaken at the Faculty of Veterinary Science, The University of Sydney, and supervised by Dr Merran Govendir

Koalas are regarded as specialist herbivores as they eat a highly restricted diet of eucalypts. Eucalypts are known to contain toxic plant secondary metabolites (PSMs) such as tannins and turpenes in high concentrations. It appears that koalas absorb less nutrients from their diet relative to other herbivorous species, perhaps as a protective mechanism to minimise absorption and the effects of PSMs. High concentrations of PSMs in foliage also appear to inhibit foraging by koalas and PSMs become elevated (and nutrient content decreases) in eucalypts when their normal environment is disturbed. Therefore the koala's ability to use certain habitats may be determined in part, by the degree to which they can cope with these toxins.

So it was not surprising, that when treating koalas with antibiotics for infectious diseases for a previous project, the investigators observed that normal dog and cat dose rates for oral medication failed to result in detectable blood concentrations in koalas. Using the treatment of koalas with appropriate oral medication as a model, the investigators hope to confirm that there is a reduced absorption of oral medication (xenobiotics) and explain why this it occurs. Is the reduced absorption of medication due to gut factors such as the presence of concentrated eucalypt ingesta, or other gut environment factors such as types and function of gut bacteria or gut pH conditions? Or is the reduced absorption due to gut cellular pumps that prevent absorption of medication, or once the medication is absorbed, does the liver rapidly break down the drug molecules so that they are no longer detectable in the blood in their original form, or is the reduced oral absorption a combination of all or some of these factors?

Another unknown in the existing knowledge is that current dose rates of both oral and injectable medications used to treat disease in koalas have never been scientifically determined, i.e. pharmacokinetic profiles for common agents have not been documented. Therefore this investigation will also seek to optimise the dose rate and dose frequency of various medications for koalas by both the oral and injectable routes.

Therefore the specific aims of this project include

1. to investigate the rate of liver metabolism in koalas by comparing the half-lives of therapeutic agents. Particularly to compare the half-lives of agents which undergo liver metabolism with those that undergo primarily kidney elimination.
2. to investigate whether P-glycoprotein pumps (cellular membrane pumps that prevent xenobiotics staying within cells) exist within the cells of the intestinal mucosa and if so, chart their distribution, density and population in various regions of the lower GIT.
3. to investigate the characteristics of the koala gut lumen itself such as the pH of the different regions of the GIT and the effect pH on drug absorption, the extent and effect of stomach digestion on absorption and to identify the principal populations of bacterial flora in the different regions of the GIT with respect to their role in absorption and
4. to determine the optimum dose rates for antimicrobial agents used to treat infectious diseases and analgesic / anti-inflammatory drugs for koalas by measuring the therapeutic concentrations obtained in the plasma and correlating these with the patient's clinical response.