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| Table 5 Some Potential Uses of PET in Kinetics and Drug Development | | Phase | | | Drug discovery and candidate choice |  |
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Species differences in receptor/enzymatic interaction and tissue energy changes |
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Validation of disease animal model in comparison to humans |
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| | Pharmacokinetics and metabolism | |
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Tissue, whole body, and excreta measurement when specifically required and other techniques are not possible |
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Comparative kinetics and physiological modeling of toxic compounds in humans |
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| | Pharmacology | |
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Relationship between plasma/tissue, active site levels and dynamic activity (receptor binding, endogenous chemical turnover, energy changes, etc.) |
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| | Toxicology | |
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Measurement in situ tissue damage in humans in comparison to animal toxicology |
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uring specific binding and activity [95]. In addition, it can measure the energy and functional activity using 18flurodeoxyglucose, which is useful in assessing disease states in tissues such as the brain or the heart. In pure kinetics terms, levels of a drug can be measured anywhere in the body in real timefor example, in the rat for phentermine [96], in the rabbit for fluconazole [97], in the monkey for dapoxetine [98], and in humans for cocaine [99]but is particularly useful when other methods are not available. One example is for a new CFC replacement for an inhalation propellant, tetrafluoroethane. As a gas, conventional distribution studies in animals are difficult and, in humans, impossible, but by using 18F and PET scanning, the regional distribution and retention in humans could be investigated on a breath-by-breath basis (Figure 11) [100]. |
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Perhaps the most important aspect of PET technology for the kinetics of the future is the measurement of the actual levels of the drug at the receptor site. Specific binding to the receptor can be obtained by obtaining an image before and after the administration of either an antagonist, which blocks the specific binding, or an inactive enantiomer, which has the same nonspecific distribution, but does not bind to the receptor. A subsequent experiment can relate plasma levels to activity at the receptor or some other measure of activity. This is particularly important when comparing animal models such as transgenic or receptor knock-out animals with human disease. |
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