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High Throughput ADME Study of New Drug Discovery

저자:   업로드:2017-09-06  조회수:

For the development of innovative drugs, the process consists of three stages and four steps: target discovery, characterization and evaluation (biological target phase); Discovery and optimization of lead compounds (drug discovery phase); ADMET (absorption, distribution, metabolism, excretion and toxicity), PK, PD studies (drug discovery and development phase); clinical trial (drug development stage).


The use of high-throughput screening technology can quickly identify the lead compounds, but by combining the chemical structure of the compound library, the first is the problem of poor structural diversity, which reduces the success rate of compound development; followed by compounds of poor drug resistance, so that a large number of Compounds were eliminated during ADME screening, increasing the cost of the experiment. Over the past 20 years, although new technologies have emerged in the drug discovery phase, there has been no substantial increase in the number of new compound entities listed each year. In addition, most of the currently established high-throughput methods are related to the type of compound structure tested and are not fully versatile.



In the drug discovery phase, there are three ways: in silico or computational method, in vitro and in vivo;


Computational Method: Although many in vivo and in vitro micro-, simplistic, and automated experimental methods have been developed that have been greatly improved in terms of analytical time, labor intensity, and number of compounds to be treated, the experimental method is still considered to be slow , costly, and the need for the synthesis of candidate compounds. The virtual screening method can be seen as an alternative method for predicting the ADME characteristics of candidate compounds. The method has high throughput or ultra-high throughput. This method includes small intestine absorption prediction; blood brain barrier (BBB) permeability prediction and Prediction of metabolic stability.

In Vitro: Over the past 10 years, in vitro methods have been widely used for the determination of permeability, bioavailability, metabolic stability, drug interactions and physico-chemical parameters. The advantage of in vitro methods is that a model of high throughput or medium flux can be established by means of micro fabrication and automation, followed by the use of tissue components from the human body to study the differences between humans and animals, to improve the success rate of drug research and development. However, in vitro studies lack the influencing factors such as blood flow, biochemical factors and various transporters in vivo. In addition, the organic solvents used in the formulation of the compounds may mask the solubility of the drug in vivo and affect the activity of the drug metabolizing enzymes. This method includes: Evaluation model of small intestine absorption; metabolic stability study; Determination of physical and chemical parameters and Study on drug interactions.

In Vivo:  In the drug discovery phase, in vivo studies have been very different from in vivo studies in terms of dose, blood collection, and animal quantity. At this stage, the purpose of in vivo research is mainly to optimize the lead compounds and to make further recommendations on the further study of candidate compounds in combination with in vitro studies. In vivo study is a low-throughput, time-consuming, large sample size and uneconomical research methods, but in vivo studies have in vitro research institute without blood flow, various factors and other factors, is the new drug research indispensable One. In vivo studies, there are two general

이전:Repeated Dose Toxicity Studies

다음에:Preclinical Pharmacokinetic Experiment