Human studies drug discovery

Future markets for biomedical microdevices for human genome studies, drug discovery and delivery in the pharmaceutical industry, clinical diagnostics, and analytical chemistry are enormous (tens of billions of U.S. dollars).In the following sections, major bioMEMS applications and microfluidics relevant to bioMEMS applications are briefly introduced. Because of the very large volume of publications on this subject, only selected papers or review articles are referenced in this entry. 

Previously, pharmacologists were constrained to the prewired sensitivity of isolated tissues for agonist study. As discussed in Chapter 2, different tissues possess different densities of receptor, different receptor co-proteins in the membranes, and different efficiencies of stimulus-response mechanisms. Judicious choice of tissue type could yield uniquely useful pharmacologic systems (i.e., sensitive screening tissues). However, before the availability of recombinant systems these choices were limited. With the ability to express different densities of human target proteins such as receptors has come a transformation in drug discovery. Recombinant cellular systems can now... 

Metabolic stability in human liver preparations may represent a suitable experimental tool to obtain relevant pharmacokinetic information in an early phase of drug discovery. Compounds which are metabolized principally by the liver can be identified and studied in more detail to determine the principal sites of biotransformation. 

Naritomi, Y. et al. Utility of microtiter plate assays for human cytochrome P450 inhibition studies in drug discovery. Drug Metab. Pharmacokin. 19 55. 

Although several physiologically based mathematical models designed to predict absorption properties have been available for several years (see Sect. 21.3), there is still only a limited number of studies describing their evaluation with respect to their ability to predict human Tabs and the relevance of how the input data (e.g., solubility and permeability) is generated in the drug discovery process. 

Different formulation principles, dosage forms, and DDSs are commonly evaluated in animal models, and attempts are made to predict human absorption on the basis of such studies.80 Human studies are also conducted in some cases to confirm predictions from animal models. Chiou et a 1.81,82 demonstrated that there is a highly significant correlation of absorption (r2 = 0.97) between humans and rats with a slope near unity. In comparison, the correlation of absorption between dog and human was poor (r2 = 0.512) as compared to that between rat and human (r2 = 0.97). Therefore, although dog has been commonly employed as an animal model for studying oral absorption in drug discovery and development, one may need to exercise caution in the interpretation of data obtained. 

Various epigenetic targets have been investigated in drug discovery approaches. So far only HDAC and DNA methyltransferase (DNMT) inhibitors are approved for the treatment of human cancer or are currently investigated in clinical studies [69]. The search for histone methyltransferase inhibitors is far less developed. 

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