CN109387573A - A kind of liquid chromatography tandem mass spectrometry quantifies tacrolimus kit and its preparation in dry blood spot - Google Patents
A kind of liquid chromatography tandem mass spectrometry quantifies tacrolimus kit and its preparation in dry blood spot Download PDFInfo
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- CN109387573A CN109387573A CN201710653898.6A CN201710653898A CN109387573A CN 109387573 A CN109387573 A CN 109387573A CN 201710653898 A CN201710653898 A CN 201710653898A CN 109387573 A CN109387573 A CN 109387573A
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- blood spot
- dry blood
- tacrolimus
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- sample
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
Abstract
The present invention provides a kind of highly sensitive liquid chromatography tandem mass spectrometries to quantify tacrolimus kit and preparation method thereof in dry blood spot.Kit is adjusted liquid and is formed by the standard curve dry blood spot of certain concentration, Quality Control sample dry blood spot, sample treatment solution, internal standard solution, mobile phase.Dry blood spot punching sampling, is first handled with solution of zinc sulfate, using ascosin as internal standard, with acetonitrile precipitation, using C18Bonded-phase silica is stationary phase, reverse-phase chromatography gradient separations are carried out by mobile phase of acetonitrile -1mM ammonium acetate, quantitative detection is carried out with mass spectrograph, ion selector channel is respectively 821.4 → m/z of m/z 768.4 (tacrolimus) and 809.6 → m/z of m/z 756.7 (internal standard ascosin).Kit of the invention, measurement sensitivity can reach 1.0ng/ml, and every methodology index can meet the needs of tacrolimus therapeutic drug monitoring in dry blood spot.
Description
Technical field
The present invention relates in a kind of dry blood spot based on dry blood spot and Liquid Chromatography-Tandem Mass Spectrometry technological development
Tacrolimus immue quantitative detection reagent box, more specifically using liquid chromatography mass technology to tacrolimus in dry blood spot
The method for carrying out accurate quantitative analysis detection.
The invention further relates to the production method of kit of the present invention and applications.
Background technique
Tacrolimus (tacrolimus, abbreviation FK506) is isolated macrolide from streptomyces culture
Class neotype immunosuppressant effectively can inhibit T lymphocyte to activate.FK506 forms a parent in conjunction with endogenous cell receptor
Exempt from plain compound, to play pharmacological action.FK506 is widely used in anti-row in the organ transplants such as liver, kidney, the heart, pancreas at present
The treatment of reprimand and self immune system related disease.The blood concentration of FK506 is related to immunosupress intensity and toxicity, no
Only therapeutic window is narrow and pharmacokinetics individual difference is big, and clinical use FK506 needs to carry out full therapeutic drug monitoring.
The method of routine clinical monitoring FK506 full blood concentration mainly has particulate to capture enzyme immunoluminescence technology at present
(microparticle enzyme immunoassay, MEIA), enzyme-linked absorption immuno analytical method (enzyme-linked
Immunosorbent assay, ELISA) and liquid chromatography mass technology (LC-MS/MS).ELISA method and MEIA method are to internal
FK506 and its metabolite generate cross-immune reaction, make the sum of actually measured result FK506 and its metabolin.LC-MS/
MS is the quantitative analysis tech rapidly developed in recent years, and there is highly selective, highly sensitive, sample process simply and automatically to change journey
High feature is spent, internal Pharmaceutical Analysis, Therapeutic Drug Monitoring, newborn's genetic disease screening and drug metabolism study are increasingly become
The practical approach in equal fields.
The patient of the organ transplants such as liver, kidney, the heart, pancreas and self immune system related disease be distributed it is in all parts of the country, especially with
Based on rural area, small and medium-sized cities, Most patients needs take medicine all the life and carry out concentration quantitative monitoring.And it is complete to carry out FK506
Mainly in tertiary hospitals and the medical inspection institute of large- and-medium size cities, long term monitoring FK506 is dense for the mechanism of the Quantitative Monitoring of blood concentration
Degree has difficulties.Whole blood sample collection is carried out using dry blood spot (Dried blood spot, DBS), with LC-MS/MS skill
Art carries out concentration quantitative, can be good at solving FK506 whole blood sample transportation cost and stability problem, really realizes strange land inspection
It surveys.
DBS i.e. by whole blood sample collect on paper jam, from the angle of Sample preservation for, dry blood cake is more more steady than whole blood
Fixed, storage and transportation cost are far below whole blood, and the sample size that dry blood spot needs to acquire is less, is needing multiple repairing weld
There is specific advantage in the detection diagnosed.Due to the simplification and higher stability of dry blood spot, many big
(such as neonatal genetic screening) is it has emerged that extremely wide application prospect in scale disorder in screening.Foreign countries are
Dry blood spot is applied in disorder in screening sample transport extensively, to a certain extent instead of the transporter of traditional whole blood
Formula.The country also gradually begins to use the transport of dry blood spot progress blood product, and multiple hospitals have used dry blood spot
It transports blood sample and carries out the disorder in screening such as AIDS (HIV), hepatitis C, glycogen storage disease such as Pompeii's disease.DBS is used for LC-MS/MS
Quantitative FK506 has not been reported.
It researchs and develops the LC-MS/MS that a kind of result is accurate, cheap, easy to operate, easy to spread and quantifies dry blood filter paper
Tacrolimus kit in piece can be widely used in China FK506 routine therapeutic drug monitoring, be able to solve rural area and
Small and medium-sized cities patient FK506 monitoring cost and stability problem really realize strange land detection, also will be helpful to improve FK506 inspection
Mass metering promotes detection method standardization and standardization.
Summary of the invention
It is dry based on dry blood spot and Liquid Chromatography-Tandem Mass Spectrometry technological development that the purpose of the present invention is to provide a kind of
Tacrolimus immue quantitative detection reagent box in blood filter paper, to meet the needs of tacrolimus therapeutic drug monitoring.
Another object of the present invention is to provide the preparation methods of mentioned reagent box.
1) technical solution
This kit is a kind of novel agent using FK506 concentration in LC-MS/MS measurement people's dry blood spot sample
Box.Kit carries out extraction pre-treatment to dry blood spot sample using ascosin as internal standard, with solution of zinc sulfate and acetonitrile, takes
Supernatant carries out LC-MS/MS detection, records FK506 and interior target peak area.Using internal standard method, according in sample to be tested
FK506/ internal standard peak area ratio can calculate FK506 concentration.Measurement result is to make in the whole blood sample of dry blood filter disc
FK506 concentration.
Kit preparation process of the invention includes the following steps:
A) preparation of tacrolimus stock solution, tacrolimus mother liquor, standard curve sample, Quality Control sample: precision weighs
10mg tacrolimus reference substance, sets in 10mL volumetric flask, acetonitrile is added to dissolve, and be diluted to scale, be configured to 1.0mgmL-1's
Tacrolimus stock solution.Precision measures tacrolimus stock solution 0.25mL, sets in 50mL volumetric flask, add whole blood (using EDTA or
ACD anti-coagulants, avoids using heparin) it is diluted to scale, it is configured to 5 μ gmL-1Tacrolimus mother liquor.Precision measures him respectively
Ke Mosi mother liquor 0,0.01,0.03,0.1,0.3,0.5mL, set in 50mL volumetric flask respectively, whole blood are added to be diluted to scale, matched
Tacrolimus standard curve concentration of specimens processed is respectively 0,1,3,10,30,50ngmL-1, packing, labeling label, completion operation.
It is accurate respectively to measure tacrolimus mother liquor 0.025,0.1,0.4mL, it sets in 50mL volumetric flask, whole blood is added to be diluted to scale, matched
Tacrolimus Quality Control concentration of specimens processed is respectively 2.5,10,40ngmL-1, packing, labeling label, completion operation.
B) preparation of standard curve dry blood spot, Quality Control sample dry blood spot: distinguished using liquid-transfering gun or capillary
Pipette standard curve sample, Quality Control sample, drop is in forming blood class on different DBS.Drop one is bled in each circle of DBS card,
Ensure to cover entirely to enclose to cut and permeates the filter paper entirely.Drop of blood only drips the one side in filter paper, not repeat in same filter paper circle
Blood in drop.It keeps filter paper hanging when dry, is horizontally fixed on desktop edge, it is sufficiently dry to guarantee, pay attention to making dry blood filter paper
Piece is far from direct heat source or daylight.In order to avoid cross contamination, card weight is not stacked and is set.After blood cake is completely dried,
It marks on dry blood spot with dry collector cards, dry collector cards is packaged using plastic packaging band, complete operation.
C) preparation of sample treatment solution: precision weighs 14.38g ZnSO4·7H2O sets in 500mL volumetric flask, adds distilled water
Dissolution, and it is diluted to scale, as 100mmolL-1Solution of zinc sulfate, packing, labeling label complete operation.
D) preparation of internal standard solution: precision weighs 1mg ascosin reference substance, sets in 50mL volumetric flask, acetonitrile is added to dissolve, and
It is diluted to scale, is configured to 20 μ gmL-1Stock solution, precision measures above-mentioned ascosin stock solution 1mL, sets 1000mL capacity
In bottle, acetonitrile is added to dissolve, and be diluted to scale, as 20ngmL-1Ascomycin solution, packing, labeling label complete behaviour
Make.
E) mobile phase adjusts the preparation of liquid: precision weighs 38.5g ammonium acetate, sets in 500mL volumetric flask, adds distillation water-soluble
Solution, and it is diluted to scale, as 1molL-1Ammonium acetate solution, packing, labeling label complete operation.
2) kit application method of the invention is as follows:
Dry blood spot punches into 1.5mL EP pipe to (radius 6mm punch makes a call to 1 hole, and radius 3mm is beaten using punch
Hole device makes a call to 3 holes), 20 μ L of sample treatment solution is added, adds 60 μ L of internal standard solution, vortex mixes 1min, stands 10min, and vortex is mixed
Even 1min is centrifuged 5min (12000rpm), and 5 μ L of supernatant sample introduction is taken to carry out LC-MS/MS quantitative analysis.
3) beneficial effect
Kit of the present invention carries out accurate quantitative analysis detection, detection to FK506 in dry blood spot using LC-MS/MS technology
As a result it is FK506 proto-drug concentration, can more accurately illustrates the relationship before drug concentration-effect treatment-adverse reaction three.Together
When, kit of the present invention realizes FK506 concentration in LC-MS/MS standard measure dry blood spot for the first time, can solve rural area and middle small city
City's patient FK506 monitoring cost and stability problem really realize strange land detection.
Detailed description of the invention
Fig. 1 tacrolimus sample process and detection process
Fig. 2 tacrolimus (A) and internal standard ascosin (B) [M+H]+Second level full scan mass spectrogram
Fig. 3 LC-MS/MS measures the exemplary ion flow graph of tacrolimus and internal standard ascosin in people's whole blood
A blank solvent
B blank whole blood dry blood spot
C standard curve 1.0ngmL-1Tacrolimus dry blood spot and 20ngmL-1Internal standard ascosin
D continuous oral gives tacrolimus capsules 2mg Grain volume dry blood spot sample (FK001) and 20ngmL-1It is interior
Mark ascosin
I. tacrolimus (FK506) II. ascosin (Internal Standard)
Fig. 4 tacrolimus representative standard curve figure
Specific embodiment
1, it is applicable in instrument
Liquid chromatography-tandem mass spectrometry instrument (LC-MS/MS) is equipped with electric spray ion source (ESI).
2, sample requirement
Venous whole sample is acquired, is placed in anticoagulant tube, prepares dry blood spot blood cake, after being completely dried, place immediately
Standby survey is sealed up for safekeeping in 2~8 DEG C of refrigerators.
3, the method for inspection
Dry blood spot Sample pretreatment:
Dry blood spot punches into 1.5mL EP pipe to (radius 6mm punch makes a call to 1 hole, and radius 3mm is beaten using punch
Hole device makes a call to 3 holes), 20 μ L of sample treatment solution is added, adds 60 μ L of internal standard solution, vortex mixes 1min, stands 10min, and vortex is mixed
Even 1min is centrifuged 5min (12000rpm), and 5 μ L of supernatant sample introduction is taken to carry out LC-MS/MS quantitative analysis.
Mass Spectrometry Conditions:
Ion source: electric spray ion source (ESI), positive ion mode detection；Ion injection electric: 5500V；Temperature: 550
℃；1 (GS1, N of gas in source2) pressure: 380kPa；Gas 2 (GS2, N2) pressure: 380kPa；Curtain gas (N2) pressure:
140kPa；Scanning mode is that multiple reaction monitors (MRM)；Collision gas (N2) pressure: Medium；Ion for quantitative analysis is anti-
It should be 821.4 → m/z of m/z 768.4 (tacrolimus, DP voltage: 45V；CE voltage: 27eV), the ion for qualitative investigation
Reaction is 821.4 → m/z of m/z 576.3 (tacrolimus, DP voltage: 45V；CE voltage: 35eV), internal standard quota ion pair m/z
809.6 → m/z 756.7 (ascosin, DP voltage: 45V；CE voltage: 30eV).
Chromatographic condition:
Chromatographic column: C18Column (20 × 4.6mm, 5 μm of partial sizes)；
Mobile phase: acetonitrile-mobile phase adjusts liquid distilled water and dilutes 1000 times, gradient elution；
Flow velocity: 0.75mLmin-1；Column temperature: 55 DEG C；Sample volume: 5 μ L.
1 condition of gradient elution of table
Measuring method:
Standard curve dry blood spot, Quality Control sample dry blood spot, sample to be tested dry blood spot are taken, before carrying out sample
After processing, 5 μ L of supernatant sample introduction is taken to carry out LC-MS/MS quantitative analysis, records ion flow graph.
Quality Control requirement:
Every 1 analysis 1 standard curve of this retinue of lot sample and 6 Quality Control samples (each 2 of high, medium and low concentration).Quality Control sample
Measurement result deviation should be less than 15%, and at most allowing 1/3 Quality Control sample results is more than above-mentioned limit, but there can be no same
In concentration Quality Control sample.If Quality Control sample measures result does not meet above-mentioned requirements, then the analysis batch sample test result cancels, weight
New detection.
4, result calculates:
Specification Curve of Increasing: with mark concentration (1.0,3.0,10.0,30.0,50.0ng of 5 standard curve samples
mL-1) it is abscissa (x), using the ratio for surveying peak area and respective internal standard peak area of 5 standard curve samples as ordinate
(y), standard curve is drawn.
The fitting of calibration curve equation: with the ratio of the actual measurement peak area and respective internal standard peak area of 5 standard curve samples
It is worth (y) to mark concentration (x) using weighting (1/x2) least square method progress linear regression.Linear regression equation: y=ax
+ b, wherein a is slope, and b is intercept, and calculates related coefficient (r), and r should be not less than 0.9900.
The calculating of the rate of recovery: the ratio of the FK506 peak area of Quality Control sample measures and internal standard peak area is substituted into above-mentioned mark
Directrix curve equation, the FK506 for calculating Quality Control sample measure concentration.The calculation formula of the Quality Control sample rate of recovery are as follows: the rate of recovery (%)
=measurement concentration/mark concentration × 100, the rate of recovery (%) should be in 100 ± 15% ranges.
Sample results calculate: the ratio of the FK506 peak area of sample and internal standard peak area is substituted into calibration curve equation, meter
Calculate the FK506 concentration of sample.
Claims (5)
1. a kind of highly sensitive liquid chromatography tandem mass spectrometry quantifies tacrolimus kit and its preparation in dry blood spot, special
Sign is standard curve dry blood spot, Quality Control sample dry blood spot, sample treatment solution, internal standard solution, stream by certain concentration
It is dynamic mutually to adjust liquid composition.
2. quantifying the preparation side of tacrolimus kit in dry blood spot according to liquid chromatography tandem mass spectrometry described in right 1
Method, it is characterised in that include the following steps: (1) tacrolimus stock solution, tacrolimus mother liquor, standard curve sample, Quality Control sample
This preparation；(2) preparation of standard curve dry blood spot, Quality Control sample dry blood spot；(3) sample treatment solution zinc sulfate is molten
The preparation of liquid；(4) preparation of internal standard solution ascosin；(5) mobile phase adjusts the preparation of liquid ammonium acetate.
3. tacrolimus quantitative detecting method in a kind of dry blood spot, comprising:
(1) dry blood spot sample preprocessing:
Dry blood spot punching sampling, is added a certain amount of sample treatment solution, and internal standard solution, vortex is added, and high speed centrifugation takes supernatant
Liquid.
(2) liquid phase separation:
A. C is used18、C8Or cyano key and silica gel make stationary phase；
B. mobile phase: acetonitrile；Methanol；Ammonium acetate；Ammonium formate；Isocratic or gradient elution；Coutroi velocity.
(3) mass spectroscopy: electric spray ion source；Atmosphere pressure chemical ion source；Positive ion mode.
4. according to tacrolimus quantitative detecting method in dry blood spot described in right 3, it is characterised in that handled with zinc sulfate
Whole blood cells carry out albumen precipitation with protein precipitants such as acetonitrile, methanol, trichloroacetic acid or perchloric acid.
5. according to tacrolimus quantitative detecting method in dry blood spot described in right 3, it is characterised in that stream used in it
Dynamic phase are as follows: acetonitrile；Methanol；Ammonium acetate；Ammonium formate；Reverse-phase chromatography is isocratic or gradient separations.
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| CN201710653898.6A CN109387573A (en) | 2017-08-03 | 2017-08-03 | A kind of liquid chromatography tandem mass spectrometry quantifies tacrolimus kit and its preparation in dry blood spot |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109884234A (en) * | 2019-04-08 | 2019-06-14 | 杭州同创医学检验实验室有限公司 | A kind of haematogenic immunity inhibition drug concentration quantitative detection method based on mass-spectrometric technique |
| CN110045037A (en) * | 2019-05-06 | 2019-07-23 | 上海药明康德医学检验所有限公司 | A kind of kit and detection method detecting nilotinib drug concentration in dry blood cake |
| CN112710766A (en) * | 2019-10-25 | 2021-04-27 | 深圳华大临床检验中心 | Method and kit for detecting five immunosuppressive agents in dried blood tablets |
| CN115267015A (en) * | 2022-05-26 | 2022-11-01 | 天津国科医工科技发展有限公司 | Sample pretreatment composition for mass spectrometry detection, application and pretreatment method |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109884234A (en) * | 2019-04-08 | 2019-06-14 | 杭州同创医学检验实验室有限公司 | A kind of haematogenic immunity inhibition drug concentration quantitative detection method based on mass-spectrometric technique |
| CN110045037A (en) * | 2019-05-06 | 2019-07-23 | 上海药明康德医学检验所有限公司 | A kind of kit and detection method detecting nilotinib drug concentration in dry blood cake |
| CN112710766A (en) * | 2019-10-25 | 2021-04-27 | 深圳华大临床检验中心 | Method and kit for detecting five immunosuppressive agents in dried blood tablets |
| CN115267015A (en) * | 2022-05-26 | 2022-11-01 | 天津国科医工科技发展有限公司 | Sample pretreatment composition for mass spectrometry detection, application and pretreatment method |
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Application publication date: 20190226 |