In a recent publication,(1) researchers at the Monash Institute of Pharmaceutical Sciences in conjunction with the Ian Wark Research Institute, University of South Australia, Monash Medical Centre and the University of Melbourne, describe drug testing in 4 beagles (and arthritic-induced rats). The study was to demonstrate bioavailability of a drug.
In pharmacology, bioavailability is a subcategory of absorption and is the amount of an administered dose of unchanged drug that reaches the circulatory system. By definition, when a medication is administered intravenously, its bioavailability is 100%. However, when a medication is administered via other routes (such as orally), its bioavailability generally decreases (due to incomplete absorption and first-pass metabolism).
The first-pass effect is a phenomenon of drug metabolism whereby the concentration of a drug is greatly reduced before it reaches the circulatory system. It is the amount of drug lost during the process of absorption which is generally related to the liver and gut wall.
After a drug is swallowed, it is absorbed by the digestive system and is carried to the liver before it reaches the rest of the body. The liver metabolises most drugs, sometimes to such an extent that only a small amount of active drug emerges from the liver to the rest of the circulatory system. This first pass through the liver thus greatly reduces the bioavailability of the drug.
In this experiment 4 beagles were used to to demonstrate the use of lipids (fatty molecules) to enhance the efficacy of a poorly water-soluble drug, celecoxib (an anti-inflammatory drug used to treat arthritis).
The oral bioavailability study involved a four-treatment study conducted on 4 male beagles aged between 6 months and 1 ½ years of age. The beagles were fasted for 24 hours prior to the study. After 24 hours, one group of dogs were fed and others continued to be fasted. The fed-treatment group were fed up to 1 hour prior to oral administration of the drug. Four oral formulations were administered with water. After the experiment blood samples were taken. To facilitate the collection of blood, an indwelling catheter was inserted into the cephalic vein (in the foreleg) of each dog and via intra jugular puncture.
Apart from the above study of the drug on the dogs, rheumatoid arthritis was induced in female rats which were then administered the drug formulations.
To induce an immunological response in the female rats, a heat-treated preparation was injected into the base of the tail. Disease progression was monitored daily and animals were lightly anesthetised to facilitate measurement of swelling at the ankle and footpad. The drug was given by oral gavage.
After experimentation the rats were killed by cervical dislocation and their hind legs were removed above the ankle for histological evaluation.
The researchers found that their results (i.e. the presence of lipids and enhanced bioavailability) “were consistent with previous studies conducted in dogs and humans”!
Animal welfare concerns
There would have been obvious distress for the rats involved in this experimentation. They were subjected to injections, pain from induced arthritis and from the immobility due to the swelling. They would also likely to have had a immunological response to the anaesthesia.
The fate of the beagles is unknown however to be used in an on-going cycle of experiments in unfamiliar surrounds is of animal welfare concern.
There are significant species differences in the liver function between rats, dogs and people, to the point where it is impossible to predict first-pass effect from one species to another (2).
In summarising this research, Dr Andre Menache, says :
“Let’s look at a real-life example of what we are talking about. Drug-induced liver damage in people is the most frequent reason cited for the withdrawal from the market of an approved drug, and it also accounts for more than 50% of acute liver failure in people in the United States (3).
In other words, liver damage to people is caused by drugs after they were tested on rats and beagle dogs, as required by law.
Based on data from the pharmaceutical industry, the rat and dog experiments reveal liver damage approximately 50% of the time (4, 5). That’s exactly the same result one would expect from tossing a coin.
Could it get any worse than that? Yes, it gets worse. The results of drug testing may be different on male rats and male beagle dogs compared with females, due to differences in liver function between males and females (6, 7). That makes animal testing even less reliable than a coin toss.”
The experiment was funded by a substantial grant by the National Health and Medical Research Council (NHMRC) and the Australian Research Council (ARC) – both taxpayer funded federal organisations.
What you can do:
Please write to the following bodies, asking that they no longer fund unscientific animal-based experiments.
GPO Box 142
Canberra ACT 261
Australian Research Council
GPO Box 2702
1. Nguyen, Tan, Santos, Ngo, Edwards, Porter, Prestidge, Boyd (2013) Silica-lipid hybrid (SLH) formulations enhance the oral bioavailability and efficacy of celecoxib: An in vivo evaluation Journal of Controlled Release 167, 85-91
2. 1. Philos Ethics Humanit Med. 2009 Jan 15;4:2. doi: 10.1186/1747-5341-4-2. Are animal models predictive for humans? Shanks N, Greek R, Greek J.
4. Olson H, Betton G, Robinson D, Thomas K, Monro A, Kolaja G, Lilly P, Sanders J, Sipes G, Bracken W, Dorato M, Van Deun K, Smith P, Berger B, Heller A. Concordance of the toxicity of pharmaceuticals in humans and in animals. Regul Toxicol Pharmacol. 2000;32:56–67. doi: 10.1006/rtph.2000.1399.