Preclinical Pharmacokinetic Experiment

著者：   アップロード：2017-09-06  閲読回数：

Non-clinical pharmacokinetic studies are based on animal, external and human research methods to reveal the dynamic changes in drugs in vivo, to obtain the basic pharmacokinetic parameters of drugs to elucidate the absorption, distribution, metabolism and excretion of drugs process and characteristics. The main contents of nonclinical pharmacokinetic studies include plasma concentration-time curve determination, absorption, distribution, excretion, plasma protein binding, biotransformation and drug metabolism.

Experimental Animals: Non-clinical pharmacokinetic studies are best to choose animals with similar genetic backgrounds and metabolic processes in humans. Juvenile, age, pregnancy or disease model animals can be used to study the different age, physiological, pathological state of the pharmacokinetics of the law, no special requirements when the general choice of adult, healthy animals. Drugs that affect pharmacokinetics for specific sex or gender differences can be tested in specific sex or in both sexes, respectively. For parenteral drugs, the general should be fasted before administration for 12h, and in the test attention to the situation according to the specific conditions of uniform fasting time to avoid the resulting fluctuations in data and food effects. Oral administration should not use rabbits and other herbivores.

Test Method: The general method of nonclinical pharmacokinetic study is to administer a certain dose of a substance in a given dose of the animal and determine the body fluid (blood, urine, bile, feces, tissue, milk, saliva, cerebrospinal fluid, Aqueous humor, etc.) in order to understand the pharmacokinetic characteristics of the test substance in animals. As pharmacokinetics have been involved in the discovery of new drug research and development of drugs, the development of high-throughput drug-based screening technology began to receive universal attention. At present, this work is mainly used in vitro and in vivo to carry out research.

In vitro studies are mainly around the gastrointestinal absorption characteristics, metabolic rate and extent, as well as metabolic enzyme-related drug interactions and so on. Commonly used in vitro models and methods are: the use of human colon cancer tissue culture of Caco-2 cell lines or canine kidney-derived MDCK cells to evaluate the absorption characteristics of the drug; the use of animal intestinal tissue to establish tissue flow cell model and alienation model to evaluate the intestinal absorption characteristics of the drug; to use liver cells or liver microsomes as the enzyme source, by enzyme kinetic method or multiple time point method to evaluate the metabolic characteristics of drugs; application of liver slices, hepatocytes, subcellular components and cDNA recombinant CYPs and other enzyme sources on the drug P450 enzyme inhibition screening. In vitro screening model has the characteristics of fast and low cost, but the test results are related to the real situation of the body, and cannot obtain some important pharmacokinetic parameters.

In order to increase pharmacokinetic screening flux, it is also possible to rationalize the test protocol in animals and reduce the number of biological samples required for analysis. At present there are two main programs: box-type drug delivery and sample mixing program.

For sample collection, there are four ways: blood collection; structure sample collection; urine and fecal samples; bile collection; animal pharmacokinetic research content, the amount of data obtained from large, after the test to be summarized as follows: plasma concentration and drug - time curve; pharmacokinetic parameters; organize the distribution data; excrete data; plasma protein binding rate; metabolic data;

Non-clinical pharmacokinetic studies are reflected in drug discovery, pharmacological and toxicological studies, and clinical trials. First, in the early stages of drug screening and design, a series of candidate compounds were obtained, in addition to a simple pharmacodynamics test to study its efficacy, but also consider the pharmacokinetic factors. 

For innovative drugs, before the clinical research to be metabolized, especially as a prod rug drug, due to the body in the efficacy and toxicity of its active metabolite, before the need for its active metabolite structure, quantity, metabolism Pathways and other in-depth and meticulous research. However, for metabolic elimination-based drugs, the purpose of its metabolism is only to eliminate, metabolites do not have biological activity, taking into account the complex and difficult metabolic research, part of the study (such as metabolite quantification) can be completed during the clinical trial. 

Non-clinical pharmacokinetic study is one of the main basis and tools of pharmacy research. It is also necessary to consider the pharmacokinetic factors in the selection of dosage forms. If the oral absorption is not good, the drug with obvious effect is not suitable for oral preparation. The rationality of formulation and process ability can be investigated by comparative studies of pharmaceuticals (bioavailability or bioequivalence), for example, by investigating the rationality of penetration enhancers in formulations for skin administration by local absorption studies; Through the comparative study of pharmacokinetics in animals (compared with the release of the preparation or the release of sustained-release formulations) to preliminary study of the feasibility of sustained-release formulations prescription. On the other hand, the characteristics of the dosage form, the excipients and preparation techniques used in the specific preparations are also important factors that affect the drug. Therefore, it can also change the pharmacological properties of the drug by means of pharmacy to make it more suitable for the clinical application.

上の：High Throughput ADME Study of New Drug Discovery

下に：Researchers Reveal Key Role for RSF1 Protein in Silencing Genes