Animal Test Models

Biosimulation in Drug Development. Edited by Martin Bertau, Erik Mosekilde, and Hans V. WesterhofF Copyright 2008 WILEY-VCH Verlag GmbH Co. KGaA, Weinheim ISBN 978-3-527-31699-1 

Mammalian metabolism itself involves biotransformations of (generally hydrophobic) drugs in liver cells, kidney, and other organs to more polar, hydrophilic derivatives in order to allow excretion from the body. This process involves two types of reactions, classified as Phase I (functionalization) and Phase II (conjugation). This has been intensively reviewed and is covered by standard textbooks in pharmacology and pharmacy. 

Traditionally, drug metabolism studies rely on the use of model systems to predict the intermediates and products of dmg metabolism in humans. For these purposes whole animal systems are in use, especially small laboratory animal models (e.g. rat, dog, cat, guinea pig, rabbit). In vitro studies are generally used to complement and specify the data obtained using perfused organs, tissue or cell cultures, and microsomal preparations. As discussed in more detail later, microorganisms can be used as model systems as well. 

In the following, we give a short introduction to experimental and computational approaches to deciphering metabolic fates of drugs, as employed right now. Afterwards, we introduce the experimental basis and computational work of our own approach before concluding with an example application. 

Furthermore, although it is recognized that the use of animals in experiments is indispensable, it raises deep ethical concerns. Therefore, current approaches strive e.g. towards more efficient animal test models, not only to provide more detailed information with respect to potential drug metabolism and pharmacokinetics in man, but also to decrease the number of experiments necessary [8]. 

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Whole-animal test models are commonly used to determine the potential carcinogenicity of an agent (see Chapter 14). Animal models provide a platform to evaluate cancer outcomes after long-term exposure to the agent at various doses, as well as to identify possible modes of action. Although epidemiologic studies are favored... 

The extrapolation of animal toxicological data to man is always tenuous, but for obvious reasons, animal test models are necessarily used. Unfortunately, there is no single animal model in which effects perfectly correlate with toxicity in children some slippage is bound to occur in comparisons between the results of animal and clinical or human studies. 

While the obvious value of in vivo animal models is clear, there also are instances—especially in cases of inflammatory arthritis, behavior, and tumor growth—where they have failed to be predictive of useful clinical activity in humans [51], For example, leukotriene (LTB4) antagonists showed activity in animal models of inflammatory arthritis yet failed to be useful in rheumatoid arthritis [52]. Similarly, dopamine D4 antagonists showed activity in animal behavior models previously predictive of dopamine D2 antagonists in schizophrenia. However, testing of dopamine D4 antagonists showed no efficacy in humans [53]. 

Andersen ME, Kirshnan K. 1994. Relating in vitro to in vivo exposures with physiologically based tissue dosimetry and tissue response models. In Salem H,ed. Animal test alternatives Refinement, reduction, replacement. New York, NY Marcel Dekker, Inc., 9-25. 

The ICRP (1994b, 1995) developed a Human Respiratory Tract Model for Radiological Protection, which contains respiratory tract deposition and clearance compartmental models for inhalation exposure that may be applied to particulate aerosols of americium compounds. The ICRP (1986, 1989) has a biokinetic model for human oral exposure that applies to americium. The National Council on Radiation Protection and Measurement (NCRP) has also developed a respiratory tract model for inhaled radionuclides (NCRP 1997). At this time, the NCRP recommends the use of the ICRP model for calculating exposures for radiation workers and the general public. Readers interested in this topic are referred to NCRP Report No. 125 Deposition, Retention and Dosimetry of Inhaled Radioactive Substances (NCRP 1997). In the appendix to the report, NCRP provides the animal testing clearance data and equations fitting the data that supported the development of the human mode for americium. 

Keywords Alternatives to animal testing, Computational toxicology, In silico, In vitro, Predictive models, QSAR models, Regulation... 

Several diverse, potent, and selective GlyT-1 inhibitors have appeared in the literature and many are reported to be efficacious in animal psychosis models. Several of these have advanced into Phase I and Phase II clinical studies. Recent Phase II results from a double-blind, 320-patient study with the investigational GlyT-1 inhibitor RG1678 (33) [17] demonstrated that the compound improved negative symptoms and social functioning of stable patients currently on atypical antipsychotic therapy and was well tolerated at all doses tested [18]. 

One potential risk that formulators run when using cosolvents as drug solubilizers is the possibility of vehicle toxicity. Each cosolvent is characterized by an acceptable concentration range, which cannot be exceeded without incurring biological damage. To avoid the requirement for in vivo testing, several in vitro models have been advanced to evaluate the relative safety of cosolvent excipients. The most useful in vitro procedure follows the hemolysis of red blood cells, which has been correlated with in vivo animal tests [87,88]. 

Animal Species/Model Selection. Safety evaluation should include the use of relevant species, in which the test article is pharmacologically active due, for example, to the expression of the appropriate receptor molecule. These can be screened with in vitro rector binding assays. Safety evaluation should normally include two appropriate species, if possible and/or feasible. The potential utility of gene knockout and/or transgenic animals in safety assessment is discussed. 

In recent years, much attention and effort have been directed toward the search for non-whole-animal tests to predict ocular irritation by drugs and chemicals. A variety of in vitro assays, as well as nonexperimental approaches, have been proposed. These model systems run the gamut of responses observed in vivo using biological... 

A number of nutrients affect bone integrity early in life. While the role of certain minerals and vitamins bearing on skeletal integrity is well established, that of protein remains controversial, especially when consumed in excessive amounts. Protein-included calciuric effect as observed in adult man and animals may also occur early in life and thus conceivably affect peak bone mass adversely, particularly when calcium intakes may be marginal. In studies reported here (test model young female rats), it was found that a diet approaching adequacy in protein and based equally on plant and animal sources would favor some parameters which bear on skeletal mass at maturity more than other combinations of protein consumed. 

The human skin model assay can provide further data on the degree of corrosiveness and allows ranking corrosives among each other. It is, therefore, accepted as a replacement method of animal tests for skin corrosion in the EU. 

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