Prediction animal bioavailability

Obach et al. [27] proposed a model to predict human bioavailability from a retrospective study of in vitro metabolism and in vivo animal pharmacokinetic (PK) data. While their model yielded acceptable predictions (within a factor of 2) for an expansive group of compounds, it relied extensively on in vivo animal PK data for interspecies scaling in order to estimate human PK parameters. Animal data are more time-consuming and costly to obtain than are permeability and metabolic clearance data hence, this approach may be limited to the later stages of discovery support when the numbers of compounds being evaluated are fewer. 

The bioavailability of selenium to a benthic deposit-feeding bivalve, Macoma balthica from particulate and dissolved phases was determined from AE data. The selenium concentration in the animals collected from San Francisco Bay was very close to that predicted by a model based on the laboratory AE studies of radiolabelled selenium from both particulate and solute sources. Uptake was found to be largely derived from particulate material [93]. The selenium occurs as selenite in the dissolved phase, and is taken up linearly with concentration. However, the particle-associated selenium as organoselenium and even elemental selenium is accumulated at much higher levels. The efficiency of uptake from the sediment of particulate radiolabelled selenium was 22%. This contrasts with an absorption efficiency of ca. 86% of organoselenium when this was fed as diatoms - the major food source of the clam. The experiments demonstrated the importance of particles in the uptake of pollutants and their transfer through the food web to molluscs, but the mode of assimilation was not discussed. 

Given the overwhelming influence of the physical properties of skin in determining bioavailabilities via the dermal route, assessment of dermal penetration is one area in metabolism and toxicology where in vitro methods can be effectively used to predict in vivo results and to screen chemicals. Apparatus and equipment exist that one can use to maintain sections of skin (obtained from euthanized animals or from human cadavers or surgical discard) for such experiments (Holland et al., 1984). These apparatus are set up to maintain the metabolic integrity of the skin sample between two reservoirs the one on the stratum comeum side, called the application reservoir and the one on the subcutaneous side, called the receptor reservoir. One simply places radiolabeled test material in the application reservoir and collects samples from the receptor fluid at various time points. 

As most drugs are preferably given orally, absorption which is complete, consistent and predictable is desirable. Although it may be possible from solubility, lipophilicity, pKa, molecular size, and animal data to make some prediction about likely absorption, only a study in humans will give quantitative data as the mechanisms of drug absorption are complex and still incompletely understood (Washington et al., 2001). It may be helpful here to distinguish between the terms absorption and bioavailability. ... 

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. 

Bioavailability from Environmental Media. The available data are insufficient to assess the bioavailability of 2,3-benzofuran from environmental media. In vitro evidence suggests that 2,3-benzofuran would be less available from organic-rich particles than from organic-poor particles (Sehnert and Risby 1988), but confirmation of this prediction with in vivo studies would be useful. Animal studies have used gavage in oil for exposure to 2,3-benzofuran (NTP 1989) but no quantitative information concerning absorption is available. Additional information on the bioavailability of... 

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. 

In contrast, different formulations of insulin and growth hormone containing the same active ingredient exhibit significant differences in bioavailability [20]. Additionally, the inability to adequately predict immunogenic responses from in vitro data or animal studies remains a concern. 

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. 

Usable methods for measuring ecotoxicity are necessary for the development of efficient strategies for bioremediation. The toxicity of soils to animals, however, cannot always be predicted by knowing only the contaminants and their concentrations (Charrois et al., 2001). There is a need for methods that will determine the risk due to contaminants that are actually bioavailable, so that the environment can be protected without unacceptably high clean-up costs. Future regulations should consider not... 

Accurate exposure and biological monitoring data are crucial to the evaluation of residential exposure and risk estimates since the potential health risks associated with a pesticide depend on the amount of exposure to the pesticide, its toxicity and the susceptibility of the exposed population. Prediction of whether adverse health effects will occur in humans can be made by comparing the exposure estimate to the No Observed Adverse Effect Level (NOAEL) derived from the animal toxicity data. Uncertainty arises from the input data used in an assessment, e.g. variability in time-activity patterns, contact with exposure media, bioavailability, exposure duration, frequency of product use and differences in the route of exposure in humans from that in the animal studies (since absorption, distribution, metabolism and elimination kinetics may differ substantially by exposure route). 

The discovery process for compound X, which is efficacious in a number of in vivo models, is again an illustration of how allometric considerations can enhance the development process. The whole brain concentrations of this compound are in equilibrium with plasma concentrations within 5 min after dosing, and it is also eliminated from the brain in equilibrium with the declining plasma concentration. We also know that compound X is 80% orally bioavailable in rats and dogs (see above) and has linear (first-order elimination) and predictable pharmacokinetics in animals. 

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