CN109946404A - Liquid Chromatography-Tandem Mass Spectrometry detects the method and detection reagent of imatinib mesylate blood concentration in blood plasma - Google Patents
Liquid Chromatography-Tandem Mass Spectrometry detects the method and detection reagent of imatinib mesylate blood concentration in blood plasma Download PDFInfo
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Abstract
The invention discloses the methods and detection reagent of imatinib mesylate blood concentration in a kind of Liquid Chromatography-Tandem Mass Spectrometry detection blood plasma, the described method comprises the following steps: ((I) preparing standard solution；(II) prepares inner mark solution；(III) sample preprocessing；(IV) Specification Curve of Increasing；(V) measures imatinib mesylate blood concentration in blood plasma.The detection reagent includes mobile phase A, Mobile phase B, standard solution and inner mark solution.The present invention provides the method for imatinib mesylate blood concentration in a kind of Liquid Chromatography-Tandem Mass Spectrometry detection blood plasma, this method Imatinib and internal standard compound carbamazepine can be kept completely separate, and small, the rate of recovery and precision height are influenced by endogenous substance impurity peaks.
Description
Technical field
The invention belongs to the detection methods of imatinib mesylate blood concentration, and in particular to a kind of liquid chromatography tandem matter
The method and detection reagent of imatinib mesylate blood concentration in spectrum detection blood plasma.
Background technique
Imatinib mesylate (imatinib) is the small molecule tyrosine kinase inhibitor of the first generation.Methanesulfonic acid she horse replace
Buddhist nun is aiming chronic myelogenous leukemia (CML) nosogenetic small molecule targeted drug, while being to recommend to shift, again for treating
Send out, can not cut off etc. gastrointestinal stromal tumor (GIST) fiest-tire medication and postoperative adjuvant drug, but the medication effect and toxicity individual difference
It is different big, such as gender, drug metabolism, and influenced vulnerable to other drugs, carry out therapeutic drug monitoring can guarantee curative effect and predict,
Mitigate toxicity, improves patients ' life quality, extends life cycle.The common detection technique of clinical examination at present is based primarily upon immune point
Analysis method, but immunoassay has birth defect to the detection of small molecule compound.Even if using monoclonal antibody, these antibody
Accurately identify that there is also difficulties for the individual molecule structure of small molecule compound.In addition, most of antibody are in detection molecules knot
When the similar compound of structure, it is easy to cause cross reaction, the metabolite of Imatinib may interfere with detection, generate false positive
Testing result.
LC-MS/MS method is the goldstandard in clinical detection, compared with clinical primary analysis method immunization, method spirit
Sensitivity is high and specificity is high, while reagent cost is cheap, detection speed is fast, detection flux is high.
Summary of the invention
The present invention is proposed to overcome disadvantage existing in the prior art, and the purpose is to provide a kind of liquid chromatogram
Tandem mass spectrum detects the method and detection reagent of imatinib mesylate blood concentration in blood plasma.
The technical scheme is that
A kind of method that Liquid Chromatography-Tandem Mass Spectrometry detects imatinib mesylate blood concentration in blood plasma, comprising the following steps:
(I) preparing standard solution
Imatinib mesylate standard items are weighed, are dissolved with methanol, standard solution is configured to；
(II) prepares inner mark solution
Carbamazepine is weighed, is dissolved with methanol, inner mark solution is configured to；
(III) sample preprocessing
Carbamazepine is drawn with pipettor precision to be added in blood plasma, is vortexed after mixing, and methanol is drawn with pipettor, by blood plasma
Albumen is precipitated, and be vortexed concussion, sufficiently after extraction, is centrifuged, is obtained with syringe Aspirate supernatant with membrane filtration after centrifugation
Sample, and be injected into sample injection bottle, it is to be analyzed；
(IV) Specification Curve of Increasing
The standard solution of various concentration is configured, each concentration is added separately in centrifuge tube containing blood plasma, is vortexed and is mixed；It mixes
After be added inner mark solution, be vortexed and mix, draw methanol with pipettor, the albumen of blood plasma is precipitated, be vortexed concussion, sufficiently extracts
Afterwards, it is centrifuged, syringe Aspirate supernatant is used after centrifugation, with membrane filtration, sample is injected into sample injection bottle, with liquid chromatogram string
Joining mass spectrum, sample introduction is analyzed, and using Imatinib mass concentration as abscissa, the peak area ratio of Imatinib and internal standard compound is vertical sits
Mark draws standard curve；
The analysis condition of the liquid chromatogram are as follows:
Chromatographic column: Agilent InfinityLab Poroshell 120 SB-C18 (4.6*50mm) 2.7-Micron；
Mobile phase: mobile phase A is the formic acid of volume fraction 0.2%, and Mobile phase B is acetonitrile；
Flow velocity: 0.5ml/min；
Sample volume 10ul；
Detection wavelength 282,272；
35 DEG C of column temperature；
Liquid chromatogram elution requirement: the volume ratio of mobile phase A and Mobile phase B is gradually equal from 70:30 in the min of 0 min ~ 1.5
It is even to drop to 10:90；The volume ratio of mobile phase A and Mobile phase B is maintained at 10:90 in the min of 1.5 min ~ 4.5；4.5
The volume ratio of mobile phase A and Mobile phase B gradually uniformly rises to 70:30 from 10:90 in the min of min ~ 5；In the min of 5 min ~ 8
The volume ratio of interior mobile phase A and Mobile phase B is maintained at 70:30；
The mass spectrographic analysis condition are as follows:
Ion source: ESI+；
Detection pattern: polyion reaction monitoring；
Monitor ion pair: 494.3 → m/z of m/z 394.2 (1), m/z237.3 → m/z194.1 (2)；
Fragmentation voltage: 100v(1), 135v(2)；
Collision energy: 20ev(1), 15ev(2)；
Dry temperature degree: 350 DEG C；
Dry gas stream speed: 8L/min；
Atomization gas pressure: 30psi；
Capillary voltage: 4kv；
(V) measures imatinib mesylate blood concentration in blood plasma
According to the analysis condition and mass spectrographic analysis condition of the liquid chromatogram in step (IV), pretreated sample is surveyed
It is fixed, obtain imatinib mesylate blood concentration in sample blood plasma.
The volume ratio of carbamazepine, blood plasma and methanol is 1:10:40 in step (III) sample preprocessing.
20mmol/L ammonium acetate is added in the mobile phase A.
For the detection reagent of imatinib mesylate blood concentration in Liquid Chromatography-Tandem Mass Spectrometry detection blood plasma, the inspection
Test agent includes mobile phase A, Mobile phase B, standard solution and inner mark solution；The mobile phase A is the formic acid of volume fraction 0.2%
Solution, and ammonium acetate is wherein added, the concentration of ammonium acetate is 20mmol/L；The Mobile phase B is the second for being filtered, being ultrasonically treated
Nitrile；The standard solution is the methanol solution of imatinib mesylate standard items；The inner mark solution is the methanol of carbamazepine
Solution.
The beneficial effects of the present invention are:
The present invention provides a kind of Liquid Chromatography-Tandem Mass Spectrometry detection blood plasma in imatinib mesylate blood concentration method and
Detection reagent, this method Imatinib and internal standard compound carbamazepine can be kept completely separate, and be influenced by endogenous substance impurity peaks small, be returned
Yield and precision are high.
Detailed description of the invention
Fig. 1 is the chromatogram of Imatinib and carbamazepine in specificity experiment of the present invention；
Fig. 2 is that Imatinib detects linear relationship chart in Linear Experiment of the present invention.
Specific embodiment
With reference to the accompanying drawings of the specification and embodiment to Liquid Chromatography-Tandem Mass Spectrometry of the present invention detection blood plasma in methanesulfonic acid she
The method and detection reagent of imatinib blood concentration are described in detail:
Embodiment 1
A kind of method that Liquid Chromatography-Tandem Mass Spectrometry detects imatinib mesylate blood concentration in blood plasma, comprising the following steps:
(I) preparing standard solution
Imatinib mesylate standard items 10mg is weighed, is set in 10ml volumetric flask, adds proper amount of methanol dissolution and constant volume, shakes up, i.e.,
The standard items stock solution that concentration is 1mg/ml is obtained, 4 DEG C of refrigerators is set and saves.
(II) prepares inner mark solution
Carbamazepine 10mg is weighed, is set in 10ml volumetric flask, proper amount of methanol dissolution and constant volume are added, shaking up to get concentration is 1mg/
The internal standard stock solution of ml is set 4 DEG C of refrigerators and is saved.Preceding methanol dilution is tested to 500ng/ml use.
(III) sample preprocessing
Blood plasma 200ul is drawn with the pipettor precision of 200ul, the 500ng/ after being diluted is drawn with the pipettor precision of 20ul
M carbamazepine inner mark solution 20ul is added in 200ul blood plasma, is vortexed after mixing 30s, is drawn with the pipettor of 1000ul
The albumen of blood plasma is precipitated 800ul methanol, and the concussion 3min that is vortexed is centrifuged, revolving speed 13000RPF sufficiently after extraction, is centrifuged
10min fills out Aspirate supernatant with 1ml syringe after centrifugation, and with membrane filtration, sample is injected into 300ul sample injection bottle, sample introduction point
Analysis；
(IV) Specification Curve of Increasing
Chromatographic condition:
Chromatographic column: Agilent InfinityLab Poroshell 120 SB-C18 (4.6*50mm) 2.7-Micron；
Mobile phase: mobile phase A: 0.2% formic acid (20mmol/L ammonium acetate), Mobile phase B: acetonitrile；
Flow velocity: 0.5ml/min；
Sample volume: 10ul；
Detection wavelength: 282,272；
Column temperature: 35 DEG C.
Liquid chromatogram elution requirement:
| Time (min) | A% | B% | Flow velocity ml/ml |
| 0 | 70 | 30 | 0.5 |
| 1.5 | 10 | 90 | 0.5 |
| 4.5 | 10 | 90 | 0.5 |
| 5 | 70 | 30 | 0.5 |
| 8 | 70 | 30 | 0.5 |
Mass Spectrometry Conditions:
Ion source: ESI+；
Detection pattern: polyion reaction monitoring (MRM)；
Monitor ion pair: 494.3 → m/z of m/z 394.2 (1), m/z237.3 → m/z194.1 (2)；
Fragmentation voltage: 100v(1), 135v(2)；
Collision energy: 20ev(1), 15ev(2)；
Dry temperature degree: 350 DEG C；
Dry gas stream speed: 8L/min；
Atomization gas pressure: 30psi；
Capillary voltage: 4kv.
To be diluted to blank plasma containing concentration be respectively 3200,1600,800,400,200,100,50,25,12.5,
The serial blood sample of 6.25ng/ml takes 32ul prepared standard solution, 968ul methanol is added, by the standard solution of 1mg/ml
Be diluted to 32000ng/ml, below concentration go down by 2 times of dilutions, respectively 16000ng/ml, 8000ng/ml, 4000ng/ml,
2000ng/ml, 1000ng/ml, 500ng/ml, 250ng/ml, 125ng/ml, 62.5ng/ml, each concentration are added separately to contain
In the centrifuge tube for having 180ul blood plasma, it is vortexed and mixes 30s；The internal standard standard solution for being diluted to 500ng/ml is added after mixing, is vortexed
30s is mixed, 800ul methanol is drawn with the pipettor of 1000ul, the albumen of blood plasma is precipitated, be vortexed concussion 3min, sufficiently extracts
Afterwards, it is centrifuged, revolving speed 13000RPF10min, there is 1ml syringe to fill out Aspirate supernatant from the complete heart, with membrane filtration, sample injection
Into 300ul sample injection bottle, sample introduction is analyzed, using Imatinib mass concentration as abscissa, the peak area of Imatinib and internal standard compound
Ratio is ordinate, draws standard curve；
(V) measures imatinib mesylate blood concentration in blood plasma
According to the analysis condition and mass spectrographic analysis condition of the liquid chromatogram in step (IV), pretreated sample is surveyed
It is fixed, obtain imatinib mesylate blood concentration in sample blood plasma.
The performance verification of methodology is carried out for the method for the present invention
One, specificity
Each 180ul of the blank plasma of separate sources is taken respectively, and totally 6 parts, in addition to replacing inner mark solution with equivalent methanol, other are pressed
The method of " sample preprocessing " operates, and then sample introduction measures.Standard solution is taken, is configured to content 500ng/ml's with blank plasma
Minimum quantitative limit blood sample, sample introduction measurement.Under this experiment condition, Imatinib and internal standard compound carbamazepine can be kept completely separate, and
It is influenced by endogenous substance impurity peaks small.The appearance time of Imatinib is 3.20 min, the appearance time 3.56 of carbamazepine
Min, as shown in Figure 1.
Two, Linear Experiment
Take standard solution, with blank plasma be diluted to containing concentration be respectively 3200ng/ml, 1600ng/ml, 800ng/ml,
The serial blood sample of 400ng/ml, 200ng/ml, 100ng/ml, 50ng/ml, 25ng/ml, 12.5ng/ml, 6.25ng/ml, with her
Imatinib mass concentration is abscissa, and the peak area ratio of Imatinib and internal standard compound is ordinate, with corresponding each point mass
Concentration is that abscissa draws linearity of regression equation, and linear relationship chart is as shown in Figure 2.
According to result calculate Imatinib standard curve regression equation be y=1.5947x+0.026, R=
0.9995。
Three, the rate of recovery and precision
(1) absolute recovery:
A certain amount of Imatinib reference substance is added in blank plasma, be made into it is basic, normal, high be respectively 0.5ug/ml, 1ug/ml,
It each 5 parts of the sample of 2ug/ml mass concentration, is handled by " sample preprocessing " method, then prepares the Imatinib control of respective concentration
Two groups of peak areas are compared with methanol dilution sample introduction, are calculated the absolute of Imatinib by the pure solvent solution of product and internal standard compound
The rate of recovery.
(2) relative recovery:
Each 5 parts of sample that basic, normal, high concentration is 0.5ug/ml, 1ug/ml, 2ug/ml mass concentration are prepared, by " sample is located in advance
Reason " method processing there emerged a respective concentration according to standard curve calculating, calculate relative recovery.
(3) precision:
Blank plasma is taken, prepares the Imatinib plasma sample each 5 that mass concentration is 0.5ug/ml, 1ug/ml, 2ug/ml respectively
Part, it is handled by " sample preprocessing " method, in a few days sample introduction, investigates withinday precision, METHOD FOR CONTINUOUS DETERMINATION three days, retinue standard was bent
Line investigates day to day precision, and the rate of recovery and precision the results are shown in Table 1.
The rate of recovery of Imatinib and precision (n=10) in 1 blood plasma of table
The present invention provides the methods of imatinib mesylate blood concentration in a kind of Liquid Chromatography-Tandem Mass Spectrometry detection blood plasma, should
Method Imatinib and internal standard compound carbamazepine can be kept completely separate, and small, the rate of recovery and precision are influenced by endogenous substance impurity peaks
Degree is high.
Claims (4)
1. a kind of method of imatinib mesylate blood concentration in Liquid Chromatography-Tandem Mass Spectrometry detection blood plasma, it is characterised in that:
The following steps are included:
(I) preparing standard solution
Imatinib mesylate standard items are weighed, are dissolved with methanol, standard solution is configured to；
(II) prepares inner mark solution
Carbamazepine is weighed, is dissolved with methanol, inner mark solution is configured to；
(III) sample preprocessing
Carbamazepine is drawn with pipettor precision to be added in blood plasma, is vortexed after mixing, and methanol is drawn with pipettor, by blood plasma
Albumen is precipitated, and be vortexed concussion, sufficiently after extraction, is centrifuged, is obtained with syringe Aspirate supernatant with membrane filtration after centrifugation
Sample, and be injected into sample injection bottle, it is to be analyzed；
(IV) Specification Curve of Increasing
The standard solution of various concentration is configured, each concentration is added separately in centrifuge tube containing blood plasma, is vortexed and is mixed；It mixes
After be added inner mark solution, be vortexed and mix, draw methanol with pipettor, the albumen of blood plasma is precipitated, be vortexed concussion, sufficiently extracts
Afterwards, it is centrifuged, syringe Aspirate supernatant is used after centrifugation, with membrane filtration, sample is injected into sample injection bottle, with liquid chromatogram string
Joining mass spectrum, sample introduction is analyzed, and using Imatinib mass concentration as abscissa, the peak area ratio of Imatinib and internal standard compound is vertical sits
Mark draws standard curve；
The analysis condition of the liquid chromatogram are as follows:
Chromatographic column: Agilent InfinityLab Poroshell 120 SB-C18 (4.6*50mm) 2.7-Micron；
Mobile phase: mobile phase A is the formic acid of volume fraction 0.2%, and Mobile phase B is acetonitrile；
Flow velocity: 0.5ml/min；
Sample volume 10ul；
Detection wavelength 282,272；
35 DEG C of column temperature；
Liquid chromatogram elution requirement: the volume ratio of mobile phase A and Mobile phase B is gradually equal from 70:30 in the min of 0 min ~ 1.5
It is even to drop to 10:90；The volume ratio of mobile phase A and Mobile phase B is maintained at 10:90 in the min of 1.5 min ~ 4.5；4.5
The volume ratio of mobile phase A and Mobile phase B gradually uniformly rises to 70:30 from 10:90 in the min of min ~ 5；In the min of 5 min ~ 8
The volume ratio of interior mobile phase A and Mobile phase B is maintained at 70:30；
The mass spectrographic analysis condition are as follows:
Ion source: ESI+；
Detection pattern: polyion reaction monitoring；
Monitor ion pair: 494.3 → m/z of m/z 394.2 (1), m/z237.3 → m/z194.1 (2)；
Fragmentation voltage: 100v(1), 135v(2)；
Collision energy: 20ev(1), 15ev(2)；
Dry temperature degree: 350 DEG C；
Dry gas stream speed: 8L/min；
Atomization gas pressure: 30psi；
Capillary voltage: 4kv；
(V) measures imatinib mesylate blood concentration in blood plasma
According to the analysis condition and mass spectrographic analysis condition of the liquid chromatogram in step (IV), pretreated sample is surveyed
It is fixed, obtain imatinib mesylate blood concentration in sample blood plasma.
2. the side of imatinib mesylate blood concentration in Liquid Chromatography-Tandem Mass Spectrometry detection blood plasma according to claim 1
Method, it is characterised in that: the volume ratio of carbamazepine, blood plasma and methanol is 1:10:40 in step (III) sample preprocessing.
3. the side of imatinib mesylate blood concentration in Liquid Chromatography-Tandem Mass Spectrometry detection blood plasma according to claim 1
Method, it is characterised in that: 20mmol/L ammonium acetate is added in the mobile phase A.
4. for imatinib mesylate in the detection blood plasma of Liquid Chromatography-Tandem Mass Spectrometry described in claims 1 to 3 any one
The detection reagent of blood concentration, it is characterised in that:
The detection reagent includes mobile phase A, Mobile phase B, standard solution and inner mark solution；
The mobile phase A is the formic acid solution of volume fraction 0.2%, and wherein adds ammonium acetate, and the concentration of ammonium acetate is
20mmol/L；
The Mobile phase B is the acetonitrile for being filtered, being ultrasonically treated；
The standard solution is the methanol solution of imatinib mesylate standard items；
The inner mark solution is the methanol solution of carbamazepine.
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| CN111665315A (en) * | 2020-06-18 | 2020-09-15 | 上海大学 | Detection and analysis method of anticancer drugs in natural water body |
| CN111665315B (en) * | 2020-06-18 | 2022-11-22 | 上海大学 | Detection and analysis method of anticancer drugs in natural water body |
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