ADMET absorption, distribution metabolism, elimination, and

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

Tab8.2 Clinical ADMET (Absorption, Distribution, Metabolism, Elimination and Toxicity) characteristics of atenolol, betaxolol, celiprolol, and nebivolol. For details and reference sources, see the text. 

Identification of additional predictive and simulation tools to leverage curated data, for example, ADMET (absorption, distribution, metabolism, elimination and toxicology). Rapid identification of privileged fragments that lead to selection of compounds of high interest for a specific target. 

A series of rate constants (k, h ) are currently used in physiologically based models to describe the transfer of a dose to the stomach and then its distribution to the various regions of the small intestine. This compartmental approach was used by Timchalk et al. (2002) to predict the ADMET (absorption, distribution, metabolism, elimination, and toxicity) of chlorpyrifos in rats and humans. Zhang et al. (2007) chose a compartmental transit and absorption GI model for carbofuran. The model incorporated the majority of the GI, including colon, duodenum, lower small intestine, and stomach lumen (food flow, L h , and volumes, L) and walls (volume, percent). Yu et al. (1996) developed one of the first compartmental absorption and transit (CAT) models that were described by a set of differential... 

Hydrophobicity plays such an important role in drug absorption and distribution that it will be addressed in some depth. In combination with other relevant electronic, topological, steiic and hydrogen bond descriptors, hydrophobicity wields an important role in absorption, distribution, metabolism, elimination and toxicity (ADMET) phenomena. 

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. 

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]. 

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],... 

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