Animal Models in vivo

Ethical issues as well as difficulty in obtaining enough human nasal tissue specimens have called for the need to use alternative in vitro and in vivo methods. Various in vivo animal models and in vitro excised tissue models have been described in the literature for nasal drug transport studies. However, due to the difficulty in both controlling the experimental conditions in in vivo animal models and obtaining intact excised tissue samples, in vitro cell culture models are also being actively developed. 

Cultured nasal cells are reliable models for drug transport and metabolism studies, since they are known to express important biological features (e.g. tight junctions, mucin secretion, cilia, and various transporters), resembling those found in vivo systems. Moreover, easy control of experimental conditions as well as separation of the permeation step from the subsequent absorption cascade is also possible. A relatively simple primary culture condition using human nasal epithelial cells for in vitro drug transport studies has been established and applied in transport and metabolism studies of drugs. It is known that the culture condition and/or selection of culture media are critical in the recapitulation of well-differentiation features of in vivo nasal mucosal epithelium [46], 

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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]. 

A lead is variously defined in the pharmaceutical industry as a compound derived from a hit with some degree of in vitro optimization (potency in primary assay, activity in functional and/or cellular assay), optimization of physical properties (solubility, permeability), and optimization of in vitro ADME properties (microsomal stability, CYP inhibition). Moreover, a lead must have established SAR/SPR around these parameters such that continued optimization appears possible. A lead may also have preliminary PK and in vivo animal model data. However, it is the task of the lead optimization chemist to improve PK and in vivo activity to the levels needed for identification of a clinical candidate. 

Kroeber MW et al (2002) New in vivo animal model to create intervertebral disc degeneration and to investigate the effects of therapeutic strategies to stimulate disc regeneration. 

This chapter considers the effects of indolealkylamine (LSD-like) and phenyl-alkylamine (mescaline-like) hallucinogens on learned behavior. We concentrate on those approaches that have shed the most light on underlying neuronal mechanisms or that show promise of becoming useful (in vivo) animal models of hallucinogenic drug action. Thus we are selective rather than exhaustive, a luxury made possible in part because several more empirically oriented reviews have been published recently (14,16,34,35). 

The designation potential endocrine disrupter has been proposed for chemical products with an endocrine-disruption ability that is demonstrated in an in vitro assay but not confirmed in an in vivo animal model. To date, most of the available information on chemical products with endocrine disrupter activity has been generated by in vitro experiments [10]. Various existing tests and bioassays of very different types have been proposed by distinct international bodies to identify hormonal... 

The guideline acknowledges that there could be very unusual cases in which the thorough QT/QTc study is negative but the available nonclinical data are strongly positive (e.g. hERG positive at low concentrations and in vivo animal model results... 

The degree of exposure of the fetus to a particular substance can be best assessed in human subjects, but concerns of fetal safety have restricted the use of this approach. Moreover, clinical studies cannot elucidate the various mechanisms that contribute to transplacental transport of a particular compound. There are many structural differences between the human placenta and the placenta of other mammalian species, which complicates extrapolation of data obtained from in vivo animal models to humans [7], Thus, several ex vivo and in vitro techniques have been developed to study the placental role in drug transfer and metabolism during pregnancy and there are some excellent articles that discuss these systems in detail [7], Both isolated tissues and various cell culture techniques are currently in use and these have been summarized below. 

Ando, K., Sugiyama, A., Satoh, Y., Nakamura, Y., and Hashimoto, K., Predicting drug-induced QT prolongation using a new in vivo animal model comparison of risperidone and olanzapine, /. Pharmacol. Toxicol. Methods, 49, 221, 2004. 

Kinetic solubility This pragmatic approach starts with a concentrated compound solution in pure DM SO further diluted in a buffer medium. The amount of compound in solution is measured after a few minutes incubation either by recording its UV absorbance (with or without a chromatographic step) or precipitate formation using an optical method (turbidimetry, nephelometry or flow cytometry). This approach mimics the typical path of the compound in biochemical, cellular assays or in vivo animal models. Kinetic solubility usually serves as a quality filter prior to cell based assays (see paragraphs on solubility, permeability and cellular assays). 

Marathe PH, Rodrigues AD. In vivo animal models for investigating potential CYP3A- and P-gp-mediated drug-drug interactions. Curr Drug Metab 2006 7(7) 687-704. 

Dix KJ, Coleman DP, Fossett JE et al. (2001) Disposition of propargyl alcohol in rat and mouse after intravenous, oral, dermal and inhalation exposure. Xenobiotica 31 357-375 Mathews JM, Black SR, Burka LT (1998) Disposition of butanal oxime in rat following oral, intravenous and dermal administration. Xenobiotica 28 767-777 Okuyama Y, Momota K, Morino A (1997) Pharmacokinetics of Prulifloxacin. Arzneim Forsch/Drug Res 47 276-284 Simonsen L, Petersen MB, Benfeldt E, Serup J (2002) Development of an in vivo animal model for skin penetration in hairless rats assessed by mass balance. Skin Pharmacol Appl Skin Physiol 15 414 124... 

Daptomycin has proven efficacy in a number of in vivo animal models, including soft tissue infections by MRSA, bacteraemia caused by S. aureus or vancomycin-resistant enterococci (VRE), Enterococcus faecalis pyelonephritis, MRSA osteomyelitis, MRSA and Bacillus anthracis pulmonary infections, Gram-positive endocarditis, Clostridium difficile colitis and S. pneumoniae and S. aureus meningitis.9,64 66... 

Development and validation of in vitro and/or in vivo animal models for rapid screening of molecular hbraries to identify potential medical countermeasures is another priority of the CounterACT program. These models include seizures in small mammals, models of direct lung injury from an inhaled source, animal models of cyanide intoxication, and medium throughput models of dermal or ocular injuries. It is important that models be amenable to use under GLP methodology so that the data generated are acceptable to the FDA. Since adherence to GLP standards may be expensive, earher screens to identify potential hits are usually performed under non-GLP conditions. 

The selection for organ-specific colonizing cells has been carried out mostly on in vivo animal model systems. Tumor cells are directly injected into the blood stream. In certain cases it seems advantageous that the target organ for which selection is desired... 

In vivo Animal Models Used for ADME Studies in Support of Drug Safety Evaluation 552... 

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