CN107304437A - A kind of evaluation drug metabolism and xicity related method - Google Patents
A kind of evaluation drug metabolism and xicity related method Download PDFInfo
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- CN107304437A CN107304437A CN201610255922.6A CN201610255922A CN107304437A CN 107304437 A CN107304437 A CN 107304437A CN 201610255922 A CN201610255922 A CN 201610255922A CN 107304437 A CN107304437 A CN 107304437A
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Abstract
The invention belongs to biomedicine field, it is related to the assessment technique of safety of medicine, and in particular to a kind of external drug metabolism and xicity related evaluation method, includes the metabolic stability evaluation of medicine, whether research evaluation medicine is metabolized by drug metabolic enzyme；With the toxicity assessment of drug metabolism, change of the metabolite that evaluation study medicine is produced after being metabolized by drug metabolic enzyme to the toxicity and toxicity of cell；The metabolism of external liver particle and vitro cytotoxicity are tested and combined by the present invention, need not be by identifying or extracting anabolite, the toxicity after drug metabolism can accurately be evaluated, this method can substantially use manpower and material resources sparingly financial resources, it can extensively be applied in actual metabolic toxicity assessment, be conducive to accelerating NCE initiative progress.
Description
Technical field
The invention belongs to biomedicine field, it is related to the assessment technique of safety of medicine, and in particular to a kind of external drug metabolism
And xicity related evaluation study method.
Background technology
The evaluation study of drug metabolism and its interaction is new drug under study for action（NCE）The important content of safety evaluation
One of.According to state food pharmaceuticals administration general bureau of the People's Republic of China (PRC)（CFDA）" medicine Non-clinical Pharmacokinetics are ground
Study carefully technological guidance's principle "（2014）：" Non-clinical Pharmacokinetics research is, by the research method in external and animal body, to take off
Show the dynamic rule of medicine in vivo, obtain the basic pharmacokinetic parameter of medicine, illustrate the absorption of medicine, distribution,
Metabolism and excretion（Absorption, Distribution, Metabolism, Excretion, abbreviation ADME）Process and
Feature.”.
The CFDA guideline is emphaticallyed point out：" in pharmacodynamics and toxicological evaluation, Pharmacokinetic Characteristics can enter one
Step deeply illustrates mechanism of drug action, while being also one of drug effect and the foundation of toxicological study animal selection；Medicine or active generation
Thanking production concentration data and its relevant pharmacokinetic parameter is generation, determines or illustrate drug effect or the basis of toxicity size, can
Medicine is provided to target organ effect（Drug effect or toxicity）Foundation.”
Therefore, whether NCE is metabolizedWhat metabolite isThey are either with or without toxicityIt is that NCE safety evaluations have to back
The problem of answering.
Answering the routine evaluations technology path of these key issues at present is：
1. the metabolic stability evaluation of medicine（Metabolic Stability Assay）：Whether research evaluation NCE is by medicine generation
Thank to enzyme to be metabolized
2. the identification of drug metabolite（Metabolite Identification）：If be metabolized, its metabolite is
What
3. the toxicity assessment of drug metabolite.
The challenge of above-mentioned conventional method is：Routes are evaluated for above-mentioned 3 independently to carry out, it is therefore desirable to the substantial amounts of time and into
This.Particularly in the experiment for carrying out metabolite identification and toxicity assessment, for body metabolite synthesis and extraction when
Between and cost it is very big, in the case of some, metabolite synthesis and extract all be impossible, such as, during some are poisonous
Between metabolite it is highly unstable.
The direct result of above-mentioned challenge is can not to understand the toxicity of metabolite in time in research and development early stage about innovation team
Characteristic, it is impossible to molecular modification and optimization are carried out in early stage, to avoid unnecessary failure.
Present situation based on prior art, present inventor intends providing a kind of technology path of new evaluation study, especially
It is a kind of evaluation drug metabolism and xicity related method.
The content of the invention
The purpose of the present invention be overcome prior art exist defect there is provided a kind of technology path of new evaluation study,
Specifically related to a kind of evaluation drug metabolism and xicity related method.By the metabolism of external liver particle and cell in vitro poison in this method
Property experiment combine, it is not necessary to by identification and anabolite, it is possible to accurately evaluate drug metabolism after toxicity.
This method is conducive to using manpower and material resources sparingly and accelerates NCE initiative to be in progress.
A kind of evaluation drug metabolism of the present invention and xicity related method, it includes, and investigation medicine is in people's hepatomicrosome
In metabolic condition, determine whether medicine is metabolized；If be metabolized, the evaluation of cell metabolism toxicity is further carried out.
Specifically, a kind of evaluation drug metabolism and the xicity related method of the present invention, it is characterised in that it includes step
Suddenly,
1）The metabolic stability evaluation of medicine（Metabolic Stability Assay）：
Whether research evaluation NCE is metabolized by drug metabolic enzyme
The principle of the evaluation institute foundation is
A) test system：People or experimental animal hepatomicrosome, liver particle contain internal topmost drug metabolic enzyme-CYP450 medicines
Thing oxidative metabolism enzyme system；
B) coenzyme of test system：NADPH；For CYP450 hydrogen donor, it does not have NADPH, CYP450 not to have oxidative metabolism work
Property；
C) method of testing：Will be quantitative after NCE is incubated in physiological conditions together with hepatomicrosome and CYP450 coenzyme NDAPH
Analyze NCE maternal concentration；
D) evaluating：In decline degree of the NCE maternal concentrations after above-mentioned incubation；
If NCE maternal concentration is not remarkably decreased after incubation, show that NCE is not metabolized after entering human body；
If NCE maternal concentration is remarkably decreased after incubation, show that NCE is metabolized after entering human body.Need further identification
Metabolite and its security of evaluation；
The parameter of evaluation：Half fall time（T1/2）, i.e., the time needed for NCE maternal concentrations decline 50%, therefore T1/2It is shorter
Prompting NCE is more easily metabolized；
2) toxicity assessment of drug metabolism（Drug Metabolism Based Cytotoxicity）：
The metabolism that evaluation study NCE is produced after being metabolized by drug metabolic enzyme（It is middle）Whether product is toxic to cell, toxicity
Whether change
E) test system：
External drug metabolism system：People's hepatomicrosome and CYP450 drug metabolic enzyme coenzyme NADP 11s（U.S. USFDA is followed with
State CFDA guideline）；
Vitro cytotoxicity system：Mouse 3T3 fibroblasts（Mouse 3T3 Fibrolasts, 3T3）;The system does not have medicine
Thing metabolic enzyme（Follow the external alternative of Federal Government toxicity assessment and coordinate committee member
Meeting ICCVAM guideline）；
F) shown in method of testing according to the form below 1,
Table 1
More specifically, a kind of evaluation drug metabolism of the invention and xicity related method, it includes step：
1, determinand is determined,
The determinand is selected from new drug（Including Chinese medicine）, cosmetics, food additives or environmental compound；
2, determine test system
The test system includes external drug metabolism system and vitro cytotoxicity system；
Described external drug metabolism system is selected from people's hepatomicrosome；According to International Medical ethic principle and know same in the present invention
The preparation of principle of anticipating and our unit's S.O.P.-hepatomicrosome（SOP-P-006）Prepare；The liver particle pastille of the present invention
Thing metabolism I phases enzyme, such as CYP450, and drug metabolism II phases enzyme, such as glucuronyl transferase UGT；Infective virus is not contained
Such as HIV, HBV, HCV；
Described vitro cytotoxicity system is selected from 3T3 l cells；The 3T3 Mouse fibroblast are purchased from
Shanghai cell biological research institute of the Chinese Academy of Sciences.
3, it is determined that main solvents/buffer/culture medium
Prepare the mM phosphate buffers of 1 L 100（NaPO4Buffer）：Weigh about 11.93 g anhydrous Nas2HPO4With 2.22 g mono-
It is hydrated NaH2PO4It is dissolved in 1L Mili-Q water, adjusts PH to 7.4 with phosphoric acid, or take 22.6 g Na2HPO4•7H2In O replacements
The 11.93 g anhydrous Nas stated2HPO4；Above-mentioned reagent can get out or be pre-mixed in advance if necessary progress business and dissolve
Sell；
I phase drug metabolic enzymes CYP450 coenzyme-NADPH working solutions（NADPH Solution）：Prepare 5 mM Fresh
The NADPH of pre-temperature：Weigh 83 mg NADPH and dissolve in 20 mL 37o100 mM NaPO of C pre-temperatures4Buffer (PH 7.4)；
Hepatomicrosome working solution（Liver Microsome Solution）：Take the liver that 0.78 mL protein concentrations are 20 mg/mL
Microsome adds 24.22 mL through 37o100 mM NaPO of C pre-temperatures4In Buffer (PH 7.4), the final concentration of protein is set to be
0.625 mg/mL。
4, evaluate drug metabolism and xicity related
3T3 cell culture：Pancreatin digests 3T3 cells, and regulation culture volume makes cell density reach 2.8 × 105/1mL,
Added by the amount in 100 μ L/hole in 96 orifice plates, the PBS that blank well adds 100 μ L/hole is used as reagent controls group, 37 °C, 5%
Cultivated 24 hours in CO2gas incubator, discard nutrient solution, the culture that 50 μ L contain 5% NBCS is respectively added per hole
Base, it is standby；
Experiment administration：
Test group：25 μ L testers solution are taken to be mixed with 200 μ L protein concentrations for 0.625 mg/mL hepatomicrosome solution,
37 °C of preincubates 10 minutes, after preincubate terminates, add the mM NADPH solution of 25 μ L 5 and mix to start in each sample
Reaction, 37 °C be incubated 60 minutes after the μ L of supernatant of centrifuging and taking 50 be added in 3T3 cells；
Blank control group：50 μ L5% NBCS is added in 3T3 cells；
Positive controls：Add 50 μ L 2x CPA solution（Supernatant as test group after microsomal metabolism）It is thin to 3T3
In born of the same parents, CPA is final concentration of：1、5、10、50、100、1000 μM.；
Reagent controls group：50 μ L 1%DMSO solution are added into 3T3 cells.Final concentration of the 0.5% of DMSO；
Chromogenic reaction：Put in CO2gas incubator and cultivate 4 hours, discard nutrient solution, the dimethyl diaminophenazine chloride that 250 μ L are added per hole is molten
Liquid, is cultivated 3 hours；Discard after neutral red solution, add 100 μ L dimethyl diaminophenazine chloride nitrite ion, vibration half an hour is after 570nm's
Detected in ELIASA, Cell viability is bigger, and colour developing is deeper；
5 calculate data by coefficient formula
With respect to motility rate（%）= （Experimental group O.D. values-blank control group O.D. values）/ （Reagent controls group O.D. values-blank pair
According to a group O.D. values）×l00%.
As a result show, CPA is toxic to 3T3 cells after being metabolized through mouse liver particle；This result and relevant document report
Unanimously, it was demonstrated that the feasibility for evaluating drug metabolism and xicity related method of the invention.
The external drug metabolism of the present invention and xicity related its advantage of evaluation study method have,
The metabolism of external liver particle and vitro cytotoxicity are tested and combined, it is not necessary to by identifying or extracting anabolite,
Toxicity that can be after accurate evaluation drug metabolism, this method can substantially use manpower and material resources sparingly financial resources, can be applied to extensively actual
In metabolic toxicity assessment, it is in progress beneficial to NCE initiative is accelerated.
Embodiment
Embodiment 1 is with the inventive method to endoxan（CPA）Carry out metabolic toxicity assessment
2xCPA solution is added in Mouse Liver Microsomes, is divided into 2 groups of plus-minus coenzyme NADP 11s, after 37 °C are incubated 1 hour, from
The heart takes supernatant to be added in the 3T3 cells being ready for, and continues after being incubated 4 hours, removes nutrient solution, adds dimethyl diaminophenazine chloride and is shown
Colour response；The relative motility rate of cell is calculated finally by the OD values surveyed at 570nm, judges CPA and its metabolite to 3T3 cells
Whether there is toxicity；
Result of the test is shown：In the test group of enzyme metabolic response is started without coenzyme, the motility rate of CPA parents to 3T3 cells in itself
Do not influence, illustrate do not have toxicity to 3T3 cells（As shown in table 2）, however, after enzyme is started to its metabolism through coenzyme,
Its metabolite reduces the motility rate of 3T3 cells, illustrates toxic to 3T3 cells（As shown in table 3）；Result above shows：CPA
Metabolite after being metabolized through mouse liver particle has toxicity to 3T3 cells, and this result is consistent with other document reports, it was demonstrated that
The feasibility of the technical method of the present invention.
Under the conditions of table 2. is without coenzyme NADP 11（Enzyme metabolism is not started）, toxicity of the CPA to 3T3 cells
Table 3 is added after coenzyme NADP 11（Start enzyme metabolism）, toxicity of the CPA to 3T3 cells
Embodiment 2 is with the inventive method to TAM（TOMAXIFEN；TOX）Carry out metabolic toxicity assessment
The TOX of various concentrations solution is added in hepatomicrosome, is divided into 2 groups of plus-minus coenzyme NADP 11s, 37 °C are incubated 1 hour
Afterwards, centrifuging and taking supernatant is added in the 3T3 cells of preparation, is continued after being incubated 4 hours, is removed nutrient solution, 15 are hereafter added per hole
μL 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide（MTT）, make last dense
Spend for 5 mg/mL；Cultivate again 3 hours, 150 μ L dimethyl sulfoxides are added per hole（DMSO）, horizontal vibration instrument is placed in, with per minute
The level of 50 times is shaken, and is cultivated 10 minutes at room temperature, in 570 nm densitometrics；
Result of the test is shown：In the test group of enzyme metabolic response is started without coenzyme（As shown in table 4）, TOM parents are to 3T3 cells
Toxicity be significantly greater than through coenzyme start enzyme to TOM be metabolized after test group（As shown in table 5）, result above shows：With implementation
CPA metabolism increases malicious process on the contrary, to the less toxics of 3T3 cells after TOX is metabolized through liver particle, illustrating TOX metabolism in example 1
Property is removing toxic substances；In addition, the feasibility of the method for the present invention is as a result demonstrated, and suitable for MTT and neutral red staining.
Under the conditions of table 4 is without coenzyme NADP 11（Enzyme metabolism is not started）, toxicity of the TOM to 3T3 cells
Table 5 is added after coenzyme NADP 11（Start enzyme metabolism）, toxicity of the TOM to 3T3 cells
Claims (8)
1. a kind of evaluation drug metabolism and xicity related method, it is characterised in that it includes,
1）The metabolic stability evaluation of medicine：Research evaluation medicine（NCE）Whether it is metabolized by drug metabolic enzyme；
2) toxicity assessment of drug metabolism：Evaluation study medicine（NCE）The metabolite produced after being metabolized by drug metabolic enzyme
Change to the toxicity of cell, and toxicity.
2. evaluate drug metabolism and xicity related method as described in claim 1, it is characterised in that it includes step：
Determine determinand,
The determinand is selected from new drug, cosmetics, food additives or environmental compound；
Determine test system
The test system includes external drug metabolism system and vitro cytotoxicity system；
3) main solvents/buffer/culture medium is determined
4) drug metabolism is evaluated and xicity related
Data according to the following formula
With respect to motility rate（%）= （Experimental group O.D. values-blank control group O.D. values）/ （Reagent controls group O.D. values-blank pair
According to a group O.D. values）×l00%.
3. evaluate drug metabolism and xicity related method as described in claim 2, it is characterised in that wherein described is external
Drug metabolism system is selected from people's hepatomicrosome；Described liver particle drug containing is metabolized I phases enzyme, such as CYP450, and drug metabolism II
Phase enzyme, such as glucuronyl transferase UGT；Infective virus such as HIV, HBV, HCV are not contained；Described vitro cytotoxicity system
System is selected from 3T3 l cells.
4. evaluate drug metabolism and xicity related method as described in claim 2, it is characterised in that wherein described is main
Solvents/buffer/culture medium be 100 mM phosphate buffers（NaPO4Buffer）, I phase drug metabolic enzymes CYP450's is auxiliary
Enzyme-NADPH working solutions（NADPH Solution）, hepatomicrosome working solution（Liver Microsome Solution）.
5. evaluate drug metabolism and xicity related method as described in claim 2, it is characterised in that wherein described evaluation
Drug metabolism and xicity related, including experiment administration is carried out after 3T3 cell culture：Test group is wherein set, blank control group is positive
Control group and reagent controls group, through chromogenic reaction：Data according to the following formula,
With respect to motility rate（%）= （Experimental group O.D. values-blank control group O.D. values）/ （Reagent controls group O.D. values-blank pair
According to a group O.D. values）×l00%.
6. evaluate drug metabolism and xicity related method as described in claim 1, it is characterised in that wherein drug metabolism is commented
The parameter of valency is, half fall time T1/2, i.e., the time needed for NCE maternal concentrations decline 50%, T1/2Shorter expression medicine
（NCE）More easily it is metabolized；
The toxicity assessment parameter of drug metabolism is, after cell incubation, adds dimethyl diaminophenazine chloride and carries out after chromogenic reaction, by surveying 570nm
The OD values at place calculate the relative motility rate of cell, judge medicine and its metabolite to cell whether toxicity.
7. evaluate drug metabolism and xicity related method as described in claim 6, it is characterised in that cell therein is
3T3 cells.
8. evaluate drug metabolism and xicity related method as described in claim 5, it is characterised in that wherein experimental group with it is right
Cytotoxicity according to group equally shows that metabolite does not have toxicity；The cytotoxicity of experimental group shows metabolic process less than control group
Property for removing toxic substances；The cytotoxicity of experimental group shows metabolic process to increase poison higher than control group.
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Cited By (2)
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