ADMET properties, Absorption distribution, metabolism

Hansch and Leo [13] described the impact of Hpophihdty on pharmacodynamic events in detailed chapters on QSAR studies of proteins and enzymes, of antitumor drugs, of central nervous system agents as well as microbial and pesticide QSAR studies. Furthermore, many reviews document the prime importance of log P as descriptors of absorption, distribution, metabolism, excretion and toxicity (ADMET) properties [5-18]. Increased lipophilicity was shown to correlate with poorer aqueous solubility, increased plasma protein binding, increased storage in tissues, and more rapid metabolism and elimination. Lipophilicity is also a highly important descriptor of blood-brain barrier (BBB) permeability [19, 20]. Last, but not least, lipophilicity plays a dominant role in toxicity prediction [21]. 

Among chemical-physics properties, lipophilicity is certainly a key parameter to understand and predict absorption, distribution, metabolism, excretion, and toxicity (ADMET) of NCE furthermore, it contributes to model ligand-target interactions underlying the pharmacodynamic phase [15],... 

A number of recent success stories prove that DOS compounds provide invaluable tools for target validation — see Panel B of Fig. 4. The validation of the ADMET (absorption, distribution, metabolism, excretion, and toxicology) and in vivo properties of these compounds and their value as... 

Instead, due to the multi-objective nature of drug discovery, other factors, such as absorption, distribution, metabolism, excretion, toxicity (ADMET), selectivity and cost, molecular screening libraries need to be carefully planned and a number of design objectives must be taken into account (8). In recent times, MLD efforts have been exploring the use of multi-objective optimization (MOOP) techniques capable of designing libraries based on a number of properties simultaneously (9). 

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). 

This chapter describes some of the approaches and techniques used currently to derive in silico models for the prediction of absorption, distribution, metabolism, elimination/excretion, and toxicity (ADMET) properties. The chapter also discusses some of the fundamental requirements for deriving statistically sound and predictive ADMET relationships as well as some of the pitfalls and problems encountered during these investigations. It is the intention of the authors to make the reader aware of some of the challenges involved in deriving useful in silico ADMET models for drug development. 

The increase in new structures generated each year has not resulted in the expected increase of marketed new drugs annually. This has amongst others been attributed to poor pharmacokinetic (PK) properties of the CDs, and as much as 40% of the attrition rate of CDs has been related to poor PK profiles [1]. Given this, reliable screening filters for factors such as absorption, distribution, metabolism, elimination/excretion, and toxicity (ADMET) are highly desirable [2-4], Indeed, the considerable effort that has been invested in the development of experimental absorption filters, for example, cell monolayers for permeability determinations [5, 6] and the turbidimetric method for solubility measurements [7],... 

Finding a molecule that has the right profile with regard to Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) as well as physicochemical properties. 

It is a commercial website used to compute 2,000 descriptors including absorption, distribution, metabolism, elimination and toxicity (ADMET)-relevant properties like caco-2 cell permeabihty, blood-brain barrier, human intestinal absorption, etc. [56]. It also comes with a drawing tool and libraiy builder. 

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]. 

---