Targeting assessment types

The decision on what type of screen to use in FBDD is affected by many different factors availability of protein for screening, compound selection, throughput, turnaround and rate of false positives and negatives. The resolution of these questions from target assessment directly impact the possibilities in this section. If there is not sufficient protein for a biophysical screen, a biochemical screen is the only choice. Protein that is not stable for... 

There are, of course, many other in vitro, ex vivo, and in vivo endpoints that can be employed depending on target cell type, understanding of potential for GI effects related to the primary pharmacology of the target or lesions identified from preclinical models, such as fecal microflora composition, charcoal transit time, ileum contraction, or quantification of short-circuit current with Ussing chambers. For excellent review of endpoints for assessment of GI toxicity, the reader is referred to Kapp (2008). 

The second step is to construct quantiles. As Demery (2000, 2003) shows, the results of a targeting assessment can be quite sensitive to the types of quantiles the analyst uses, be they individuals or households. Constructing these so that they contain the same number of individuals, not households, is preferable except when a previous targeting assessment... 

TABLE 6.10 Some of the Main Types of Targeting Assessments... 

A complete medical history and targeted physical examination are essential to correctly classify the type(s) of Ul present. It is important to assess the degree of annoyance due to symptoms of the patient during the assessment. The degree of annoyance to the patient may not correlate well with the results of quantitative tests such as symptom frequency/severity, use of... 

The farmer should price his product to reflect the quality, cost of production, competition, service provided, convenience and types of buyer targeted. If all of it sells, the price is too low. At least 10% of people should walk by shaking their heads. The farmer has to consider the transport needed for his product to the market, the distance involved and whether a suitable vehicle is available and can be fully loaded. Sales must be assessed after every event. Don t drive 200 miles to sell 25 chickens (Fanatico Redhage, 2002). 

The partitioning of the activated inhibitor between direct covalent inactivation of the enzyme and release into solution is an important issue for mechanism-based inactivators. The partition ratio is of value as a quantitative measure of inactivation efficiency, as described above. This value is also important in assessing the suitability of a compound as a drug for clinical use. If the partition ratio is high, this means that a significant proportion of the activated inhibitor molecules is not sequestered as a covalent adduct with the target enzyme but instead is released into solution. Once released, the compound can diffuse away to covalently modify other proteins within the cell, tissue, or systemic circulation. This could then lead to the same types of potential clinical liabilities that were discussed earlier in this chapter in the context of affinity labels, and would therefore erode the potential therapeutic index for such a compound. 

The absorption efficiency term allows estimation of the effective dose or the amount of pollutant which crosses the membrane of the exposed tissue (e.g., the lung) and reaches a target organ (e.g., the liver). For many pollutants this type of metabolic data is not available and consequently 100% absorption is a common preliminary assumption in exposure assessments. For well-studied substances such as radionuclides, a methodology for calculation of target organ doses has been developed for bone marrow, lungs, endosteal cells, stomach wall, lower intestine wall, thyroid, liver, kidney, testes and ovaries as well as for the total body. 

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