High Throughput ADME Study of New Drug Discovery

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).

High Throughput ADME Study of New Drug Discovery

The use of high-throughput ADME 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.

high-throughput adme screening

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 approaches to improving the flux: increasing the speed of analysis and reducing the number of samples. There are two things should be noticed in this method, to improve sample analysis speed and reduce the number of samples.

Preclinical ADME Studies

Medicilon’s Drug ADME/PK Assays Services

ADME Pharmacokinetics Studies

High Throughput ADME Study of New Drug Discovery

Medicilon's Drug ADME/PK Assays Services

Drug absorption, distribution, metabolism and excretion (pharmacokinetics)

What is preclinical testing?

In the process of preclinical testing of a compound or biological agent into a drug, the compound involved must go through the testing phase. First, we need to identify potential targets that can treat the disease. Then, a variety of compounds or preparations are screened out. Any compound that has shown potential as a drug for the treatment of this disease needs to be tested for toxicity before clinical testing to reduce the possibility of injury. preclinical testing What is the basis of preclinical testing? According to US Food and Drug Administration (FDA) regulations, a series of tests are required before a new drug is approved for use. In the first stage, basic research determines a hypothetical target for the treatment of a certain disease, and then screens small molecules or biological compounds to discover any substance with the potential to treat the disease. Then, a preclinical research phase followed, before which, as described above, the potential toxicity of the compou

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Inventory of the three major in vitro pharmacokinetic research methods

The metabolic properties of a compound are an essential factor in whether or not it can be used as a drug in the clinical setting, so pharmacokinetic studies of newly synthesized compounds are required in drug development. In vitro incubation with liver microsomes, recombinant CYP450 enzyme lines, and in vitro incubation with hepatocytes are some of the more common in vitro drug metabolism methods. 1. In vitro incubation method with liver microsomes The metabolic stability and metabolic phenotypes of candidate compounds in different species of liver microsomes are good predictors of the metabolic properties of compounds in vivo. They are practical tools for evaluating candidate compounds in the pre-development phase of drug development. Liver microsomes include rat liver microsomes, human liver microsomes, canine liver microsomes, monkey liver microsomes, and mouse liver microsomes. In in vitro incubation of the liver, microsomes are the "gold standard" for in vitro d

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Novel Parkinson’s Therapies Possible with New Mouse Model

Parkinson's disease (PD) is a neurodegenerative disorder that is marked by the accumulation of the protein, α-synuclein (αS), into clumps known as Lewy bodies, which diminish neural health. Now, researchers from Brigham and Women's Hospital (BWH) report the development of a mouse model to induce PD-like αS aggregation, leading to resting tremor and abnormal movement control. The mouse responds to L-DOPA, similarly to patients with PD. The team's study (“Abrogating Native α-Synuclein Tetramers in Mice Causes a L-DOPA-Responsive Motor Syndrome Closely Resembling Parkinson’s Disease”) on the use of this transgenic mouse model appears in Neuron . “α-Synuclein (αS) regulates vesicle exocytosis but forms insoluble deposits in PD. Developing disease-modifying therapies requires animal models that reproduce cardinal features of PD. We recently described a previously unrecognized physiological form of αS, α-helical tetramers, and showed that familial PD-causing missense mutati

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