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저자： 업로드：2017-09-06 조회수：
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.
