Absorption, distribution, metabolism, excretion, and toxicity

Historically, drug absorption, distribution, metabolism, excretion, and toxicity ADMET) studies in animal models were performed after the identification of a lead compound. In order to avoid costs, nowadays pharmaceutical companies evaluate the ADMET profiles of potential leads at an earlier stage of the development... 

Ekins S, Nikolsky Y, Nikolskaya T. Techniques application of systems biology to absorption, distribution, metabolism, excretion and toxicity. Trends Pharmacol Sci 2005 Apr 26(4) 202-9. 

ADMET absorption, distribution, metabolism, excretion and toxicity... 

Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET)... 

Repeating for emphasis - not aU poorly water-soluble compounds are equally solubilized by DMSO. The greaseball compounds will be much better solubilized than the brickdust compounds. The most common range of compound in DMSO stock concentrations in compound storage repositories is 2-20 mM. At conferences, organizations employing 2mM compound in DMSO stock solutions report fewer solubility problems. The downside is that the lower stock concentrations are more Hmited in utility in some absorption, distribution, metabolism, excretion and toxicity assays that require higher compound concentration. 

ADMET absorption, distribution, metabolism, excretion and toxicity BLW-ED block-localized wave function energy decomposition hERG human ether-a-go-go-related gene QSAR quantitative structure-activity relationship... 

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]. 

In the above-mentioned examples, the prediction of CYP-mediated compound interactions is a starting point in any metabolic pathway prediction or enzyme inactivation. This chapter presents an evolution of a standard method [1], widely used in pharmaceutical research in the early-ADMET (absorption, distribution, metabolism, excretion and toxicity) field, which provides information on the biotransformations produced by CYP-mediated substrate interactions. The methodology can be applied automatically to all the cytochromes whose 3 D structure can be modeled or is known, including plants as well as phase II enzymes. It can be used by chemists to detect molecular positions that should be protected to avoid metabolic degradation, or to check the suitability of a new scaffold or prodrug. The fully automated procedure is also a valuable new tool in early-ADMET where metabolite- or mechanism based inhibition (MBI) must be evaluated as early as possible. 

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],... 

In addition, bioinformatics databases have been expanded to integrate data on absorption, distribution, metabolism, excretion, and toxicity of drugs. Through these comprehensive sets of data, scientists have at their disposal powerful means to relate disease targets and their cellular functions to physiological and pathological processes. 

In this workflow, chemists want to draw or import a set of molecules, profile their molecular properties, such as computed ADME T (absorption, distribution, metabolism, excretion, and toxicity) properties, estimated activities against specific protein targets based on existing SAR models, and make selections based on the analysis of structural features and computed molecular properties of those singleton molecules. 

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). 

II. Product Summaries Simulations Plus develops simulation and predictive modeling software for in silico compound screening and for preclinical and clinical drug development in the area of Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET). The available applications include GastroPlus, ADMET Predictor, ADMET Modeler, DDDPlus, and MembranePlus. 

All of the above information will prove invaluable in determining the potential methods for rational drug delivery. Particular attention should be paid to the relative hygroscopicity of the API, of course, any stability information, as well as the impurity profile and ADMET (absorption, distribution, metabolism, excretion, and toxicity) information. In short, the more information that is available when development activities are initiated, the easier it is to avoid common pitfalls and make development decisions more rationally. 

---