ADMET properties metabolic stability

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). 

While most reports in the literature employ a modified version of Lipinski s Rule-of-Five criteria, a few have used models that are more sophisticated as part of the design. Many QSAR models have been reported in the literature for many different ADMET related properties, from solubility to permeability to hERG inhibition to metabolic stability. Several recent... 

Further analyses of large proprietary databases have focused on matched pair analysis of phenyl substituent effects on metabolic stability and on cytochrome P450, hERG inhibition, solubility and artificial membrane permeability." These studies also show that substituent lipophilicity is the dominant driver of ADMET properties. However, because of the opposing effects of physical properties (for example on solubility and permeability) there are no perfect substituents, where all ADMET properties are improved at... 

Absorption, distribution, metabolism, excretion, and toxicology (ADMET) properties determine the pharmacokinetic and safety behavior of compounds and thus to a large part, how effective a compound acts as a drug, how the compound has to be dosed, and what safety window has to be considered. Due to the decisive role of ADMET properties in lead optimization and drug development, these parameters are investigated very early by in vitro systems. For example, Caco-2 cell lines are used to estimate permeability of compounds, while liver microsomes are used to study metabolic stability of novel compounds in vitro [1,2]. 

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