ADME absorption, distribution metabolic stability

When one has to deal with a real new target, the only way to progress is to practice enough syntheses to identify the molecular features that are favorable and those that are detrimental to the activity. Such molecular variation programs can be practiced in several manners. Usually the predominant parameter wanted first is potency, but other qualities of the future drug molecules are relevant of drug optimization. One can mention selectivity, satisfactory ADME (absorption, distribution, metabolism, and excretion) and toxicity profiles, optimal physicochemical properties such as chemical stability, water solubility, and absence of polymorphs, finally the compounds must be patentable. Table 19.5, due to Baxter et al summarizes the different criteria practiced at the Astra-Zeneca company. 

Various in vitro assays are widely available for profiling distribution, metabolism, and pharmacokinetics (DMPK, also referred to as ADME absorption, distribution, metabolism, and excretion). Such properties of molecules are measured to ultimately predict their in vivo behavior. The metabolic stability of molecules is assessed routinely in drug discovery units by way of medium- to high-through-put assays using hepatic microsomes or hepatocytes obtained from different species (usually rat and/or human). Permeability assays (e.g., utilizing Caco-2 or MDCK cells) together with an assessment of efflux potential are also useful to troubleshoot unexpectedly low cell activity or can help select candidates for subsequent in vivo studies. 

In the following section, the calculation of the VolSurf parameters from GRID interaction energies will be explained and the physico-chemical relevance of these novel descriptors demonstrated by correlation with measured absorption/ distribution/metabolism/elimination (ADME) properties. The applications will be shown by correlating 3D molecular structures with Caco-2 cell permeabilities, thermodynamic solubilities and metabolic stabilities. Special emphasis will be placed on interpretation of the models by multivariate statistics, because a rational design to improve molecular properties is critically dependent on an understanding of how molecular features influence physico-chemical and ADME properties. 

Early determination of PK properties (absorption, distribution, metabolism, excretion and toxicity, ADMET) has become a fundamental resource of medicinal chemistry in the LO phase. New technologies have been developed to perform a great number of in vitro and even in silico tests. Currently, the most common early-ADME assays evaluate both physicochemical properties (such as the solubility in an opportune medium, the lipophilicity, and the p K i) and biophysical properties (such as the permeability through cellular monolayers to predict oral absorption and the metabolic stability after treatment with liver or microsomal subcellular fraction that contains oxidative cytochromes). 

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