Biological properties. ADME

Criteria for biological properties may be project specific, but ADME property and physical property criteria are generally invariant. Lead profiles will be addressed in more detail in the section on parallel optimization. 

ADME The abbreviation for absorption, distribution, metabolism, and excretion (see pharmacokinetics), affinity The tendency of one molecule to associate with another, analog A drug whose structure is related to that of another drug, but whose chemical and biological properties may be quite different. 

Solubility issues are universal for activity and property screening, both HTS and traditional bench-top assays. It significantly impairs the quality of biological assays, ADME/TOX screens and in vivo activity measurements. This chapter focuses on solubility issues and potential solutions for screening assays in early drug discovery. The effects of solubility on absorption and oral bio availability will be addressed elsewhere in this book. 

Currently, understanding the biometabolism of HTs, especially ETs, can contribute to the definition of their bioavailability and potential biological properties on humans. Although there is little information on the absorption, distribution, metabolism and excretion (ADME) of HTs in humans, trials with rodents and pigs, in vitro studies and fecal batch fermentations have contributed to understanding tannins metabolism. This fact becomes even more relevant for GTs since, to the best of our knowledge, there is a lack of studies focused on the biometabolism of GTs or GT-rich foodstuffs. 

It may not be practical to follow established guidelines for ADME evaluation. Binding proteins, immimoreactive metabolites and antibodies could interfere with the immimoassays used to measure the activity of biotechnologically-derived pharmaceuticals. The link between immunoreactivity and pharmacological activity may be difficult to establish, making the data difficult to interpret. In radiolabelled distribution studies, if the label alters the physicochemical and biological properties of the test material, its pharmacokinetic behaviour may change. These analytical difficulties may preclude accurate characterisation of the distribution, metabolism and excretion of a protein. 

The realization of sensitive bioanalytical methods for measuring dmg and metaboUte concentrations in plasma and other biological fluids (see Automatic INSTRUMENTATION BlosENSORs) and the development of biocompatible polymers that can be tailor made with a wide range of predictable physical properties (see Prosthetic and biomedical devices) have revolutionized the development of pharmaceuticals (qv). Such bioanalytical techniques permit the characterization of pharmacokinetics, ie, the fate of a dmg in the plasma and body as a function of time. The pharmacokinetics of a dmg encompass absorption from the physiological site, distribution to the various compartments of the body, metaboHsm (if any), and excretion from the body (ADME). Clearance is the rate of removal of a dmg from the body and is the sum of all rates of clearance including metaboHsm, elimination, and excretion. 

The Basic Concept of the QSAR Technique. The QSAR technique has been widely employed in modeling biological activities as well as ADME/Tox (absorption, distribution, metabolism, excretion, toxicity) properties. This approach was first introduced by Flansch et al. in 1963, on the basis of linear... 

As discussed above, it is important to try to optimize biological, physicochemical, and ADME properties in parallel. However, the data from all of these assays for the numerous compounds prepared by parallel synthesis make the interpretation of results challenging. The use of tools such as MVA helps in the effective utilization of all data in the optimization process. 

Prediction of ADME properties should be simple, since the number of descriptors underlying the properties is relatively small, compared to the number associated with effective drug-receptor binding space. In fact, prediction of ADME is difficult The current ADME experimental data reflect a multiplicity of mechanisms, making prediction uncertain. Screening systems for biological activity are typically single mechanisms, where computational models are easier to develop [1],... 

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