Bioavailability testing animal models

Although animal models can provide important information regarding the bioavailability and pharmacology of potential anticancer drugs in mammals, they are not always accurate predictors of activity against human tumor cells. In one report [27], the activity of a series of isomeric [l,2-bis(di-fluorophenyl)ethylenediamine]dichloroplatinum(II) compounds was evaluated in MXT murine mammary carcinomas in vivo the same compounds were also tested against several human cell lines in culture. The in vivo screen revealed a 2,6-difluoro-substituted compound to be the most active, whereas the 2,4-difluoro-substituted compound was most active against the human breast-cancer cell lines. It was concluded that the mouse mammary carcinoma is not an appropriate model for human breast cancers. Extreme caution must be employed when animal tumor results are used to predict activity in human tumors. 

Columbo C, Monhemius AJ, Plant JA (2008b) The estimation of the bioavailabilities of platinum, palladium and rhodium in vehicle exhaust catalysts and road dusts using a physiologically based extraction test. Sci Total Environ 389 46-51 Costa DL, Dreher KL (1997) Bioavailable transition metals in particulate matter mediate cardiopulmonary iniury in healthy and compromised animal models. Environ Health Perspect 105 1053-1060... 

The last step of the drug discovery process involves the testing of lead compounds to address issues such as efficacy, bioavailability, and safety. Testing may include in vitro assays but ultimately would require a suitable disease model and studies in animals. Many compounds may need to be designed and synthesized to identify the one compound with all the desired properties. Such a compound can be advanced to preclinical studies and eventually to the clinic. 

An ideal in vitro model for the characterization of aerosol formulations would incorporate cell types from various regions of the lung (tracheal, bronchial, and alveolar) and would facilitate simulation of deposition mechanisms by impaction, sedimentation, and diffusion of a high-metered singlebolus inhalation. In the future, such systems may reduce the need for animal studies and may offer to correlate in a predictive way the results from such in vitro tests to clinical bioavailability data after pulmonary drug delivery in vivo. 

The prediction of zinc bioavailability from complex food systems is not a simple matter. Animal bioassays and in vitro tests help us to identify factors that may enhance or inhibit zinc utilization from the diet. With simple model food systems, we can demonstrate the negative effects of phytic acid, calcium and other factors on zinc bioavailability. However, the interaction of these factors in complex food systems, and their effect on zinc status for man is not well understood at this time. 

However, drug substances for which /a may be affected by active transport processes [e.g., the efflux transporter P-glycoprotein (P-gp)] may require further model characterization to prevent misclassification of their permeability class. For example, functional expression of efflux transporters must be determined in cultured human or animal epithelial monolayers. At this time, the FDA recommends limiting the use of non-human permeability test methods to drug substances whose absorption is controlled by passive mechanisms. When applying the BCS, an apparent passive mechanism may be inferred when one of the following conditions is satisfied (i) a linear pharmacokinetic relationship between dose and a measure of bioavailability (e.g., area under the plasma concentration-time curve, AUC) is demonstrated in humans ... 

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