ADMET studies distribution, metabolism

Fig. 1 The dual role of RNAi technology in drug development process. RNAi compounds are being extensively used as a drug target discovery and validation tool. At the same time, they hold the promise of being used as drugs themselves. HTS, high-throughput screening of small molecules ADMET, absorption, distribution, metabolism, excretion, toxicity studies.

In this chapter, we will introduce some nuclear-based analytical techniques to study the charaeterization and potential risk of nanomaterials, especially the metallic ones, and their interactions with biological systems. However, it should be noticed that the study of interactions of nanomaterials with biological systems is a very new and emerging field. Publications on risk evaluation and ADMET (absorption, distribution, metabolism, excretion, and toxicity) studies of these nanomaterials sometimes can not be replicated and contradictory results can also be found. 

The most serious bottleneck in pharmaceutical development is the ability to complete ADMET (adsorption-distribution-metabolism-elimination-toxicity) studies early enough in the development process to focus resources on the best drug candidates. Of particular importance are human surrogates that can improve the probability that a drug will be successful in clinical trials. Such trials may cost more than a 100 million dollars and success at the rate of one in three rather than current values (about one in ten) would offer significant economic advantage. 

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... 

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]. 

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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