During the early phase of drug discovery and once a set of drug candidates has been isolated by chemists and computer scientists, researchers put drugs through a battery of in vitro assays to narrow down the list of the candidates even further. For instance, a common assay to predict oral absorption of a drug is the Caco-2 model, which uses human gastrointestinal cells and mimics the gut lumen and bloodstream. Also, the drug's elimination from the body, which affects its duration of action, can be monitored by incubating low concentrations of a drug and human hepatocytes in test tubes for 1 hour. Other in vitro assays or models are based on the cytochrome P450 (CYP450) system (a family of important enzymes involved in the metabolism of most drugs) and help identify which enzyme systems play a role in drug elimination.
It is true that no amount of in vitro tests carried out on human tissue and cells yet can inform on whether a drug will have equivalent properties in the whole human body. One major challenge in drug discovery is to determine the amount of a drug that has therapeutic effects without having side effects. Therefore, the only way to ascertain assumptions regarding drug safety and potency is to test it in a whole body. Yet the pharmacokinetics (Absorption-Distribution-Metabolism-Excretion (ADME)) of new drugs have been extrapolated from animal studies that have usually poor physiological relevance with human beings.
To measure pharmacokinetics, researchers administer radiolabeled compounds to animals and follow their path in the whole animal. They quantify the radioactivity in blood, plasma, all excreta, and then extrapolate doses to humans using so-called allometric body-weight scaling relationships between animals and human. Let alone the fundamental issue of cross-species differences in terms of biochemistry, genetics, anatomy, and physiology, which undermine the principle of extrapolation, the allometric body-weight scaling method itself is very unreliable and huge discrepancies between human and non-human species are observed. Even though some refined models use metabolic rates, binding, and bloodflow to make better predictions and to help select initial doses for human studies, animal models remains the principle bone of contention no matter how refined and complex the test is. In fact, there is no better substitute for man than man itself.
Fortunately, there is a revolution in march likely to change dramatically the drug discovery process by reducing the time of drug development to 5 years, by saving tens of millions of dollars and possibly hundreds more and ultimately by improving the safety and effectiveness of drugs. The first revolution is the replacement of rat, mice or any other non-human animal tissues with human tissue in an effort to refine existing in vitro tests and create new ones more reliable. The use of non-human tissue to model human biology must be scientifically justified instead of being merely taken for granted. In fact, why use animal parts when human tissue can be made available for research and development of drugs? Why study animal genes and proteins when the same work can be achieved with human genes and proteins?
The second revolution is the assessment of tissue concentrations of very low drug amounts in humans (microdosing). This technique has attracted great interest in early clinical drug development, and the issue emerged with resounding intensity following the VIOXX debacle. Microdosing calls for highly sensitive tools classified as semi-invasive such as microdialysis, and non-invasive (e.g, positron emission tomography and magnetic resonance spectroscopy). For example, positron emission tomography (PET) provides information on how the drug acts in the body, whereas accelerator mass spectrometry (AMS) provides pharmacokinetic information. In clear, humans (no longer animals) should be exposed to the compounds being tested, but at levels too low to cause any harmful health effects. Consequently, microdosing will allow safer earlier human studies while at the same time help reduce the use of animals in preclinical testing. Despite the good news for patients and lab animals, the impact on the replacement of non-human animals is still uncertain. In the name of tradition, convenience and free enterprise, too many scientists and regulators tend to cling to the 20 th century scheme of animal testing.
As we welcome the emergence of corporate interests and major investments in human-based research, one may wonder about the response of governments and academic institutions. What amount of animal replacement will we see in academic research, which is beyond any doubt outrageously wasteful and unregulated? What amount of replacement will we see in regulatory acute and chronic toxicology? Despite amazing scientific achievements to make better science, there are still administrative and political inertia slowing down the introduction of alternatives to animal testing. Such inertia calls for a vigorous expression of public opinion against the use of animals in scientific research.
Less is more: the human microdosing concept: R. Colin Garner, CEO Xceleron. Drug Discovery Today Volume 10, Issue 7 , 1 April 2005,
Pages 449-451
A small dose of our own medicine Financial Times 23 September 2005 p.14 |
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