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related to toxicity. We should therefore rethink which preclinical studies are required before administering a drug to humans for the first time. These are actually relatively few (Table 3). After a suitable but not all encompassing analytical method is developed, the basic kinetics parameters (clearance, volume, half-life, and extent and speed of absorption) can be measured in a few (~4) animals, in rats and dogs (primates for allometric scaling). These measures will provide all that is necessary for the design of initial dose ranging studies and safety studies and to compare allometric scaling predictions with those from in vitro metabolism. In vitro metabolism studies should be undertaken in animal tissues to choose toxicological species and interpret results, and in humans tissues or cell lines to measure rates and routes of in vivo metabolism, identify and produce important metabolites, and predict possible clinical problems and interactions. Protein binding in the different species, in comparison with humans, is also required to express the exposure calculations in terms of free-drug levels, although few reports have systematically shown that this approach is actually necessary. Whether this should be done ex vivo with samples actually taken from the safety studies or in vitro has similarly not been extensively studied but will, no doubt, be dependent on the sensitivity of the analytical procedure. Animal radioactivity studies in vivo should be minimal and used to confirm in vitro metabolism by the species closest to man and to undertake single-dose distribution studies for the measurement of radioactive exposure prior to human isotope investigations. In general, it can be argued that little else is required unless some specific problem needs to be answered. |
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VII. Blood Levels and Effect |
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Plasma or tissue levels and the derived pharmacokinetic parameters have little meaning unless they are related in some way to an effect, be it pharmacological or toxicological. For a long time, it has been generally assumed that there existed some direct linear relationship between drug concentrations and activity, such that doubling the one will lead to a corresponding increase in the other. This is rarely the case and even when it is the case, it is for only a small range of concentrations [61]. Indeed, it would appear that blood levels are another surrogate endpoint and too many assumptions are made about their relevance without justification. From Figure 7 and Table 4, it can be seen that measurement of circulating levels is far removed from the interaction at the receptor site. |
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The drug must dissociate from the binding to blood protein, pass through tissue membranes, and interact with nonspecific binding proteins before acting at its receptor. Despite the obvious importance of preclinical studies, particularly in pharmacology and toxicology, rarely is any attempt made to relate the |
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