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