CN111579690A - Mass spectrum detection reagent for determining mycophenolic acid content in biological sample by using mycophenolic acid-D3 as internal standard substance and using method thereof - Google Patents
Mass spectrum detection reagent for determining mycophenolic acid content in biological sample by using mycophenolic acid-D3 as internal standard substance and using method thereof Download PDFInfo
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Abstract
The invention relates to the field of medicine detection, in particular to a mass spectrometry method for determining the concentration of a medicine by using a stable isotope label as an internal standard, and more particularly relates to a mass spectrometry detection reagent for determining the content of mycophenolic acid in various biological samples by using mycophenolic acid-D3 and a using method thereof. Mycophenolic acid-D3 is mycophenolic acid marked by stable isotope (deuterium), the molecular mass number is higher than that of mycophenolic acid, the mycophenolic acid-D3 can be distinguished from the mycophenolic acid in mass spectrum detection, the extraction efficiency and the absolute matrix effect of the compound and the mycophenolic acid are very close, and the compound serving as an internal standard substance can reduce the influence of the effects of sample processing and detection process on the result to the maximum extent. The method adopts a direct acetonitrile protein precipitation method, is simple and convenient to operate, has lower cost and short time consumption; the mobile phase contains 0.1% formic acid, which is beneficial to improving the ionization efficiency of the mycophenolic acid, thereby improving the sensitivity of the method.
Description
Technical Field
The invention relates to the field of medicine detection, in particular to a mass spectrometry method for determining the concentration of a medicine by using a stable isotope label as an internal standard, and more particularly relates to a mass spectrometry detection reagent for determining the content of mycophenolic acid in a biological sample by using deuterated mycophenolic acid-D3 and a using method thereof.
Background
Mycophenolate Mofetil (MMF) has been widely used as a major immunosuppressant in the prevention and treatment of acute rejection after organ transplantation. After being absorbed orally, MMF is hydrolyzed into free active metabolite MPA under the action of plasma esterase; the latter selectively blocks T and B cell proliferation by inhibiting rate-limiting enzyme (hypoxanthine nucleotide dehydrogenase) in the guanine de novo synthesis pathway, and has significant curative effects on transplant rejection and autoimmune diseases. The individual difference of the MMF pharmacokinetics is large, and the area under the drug-time curve (AUC) is related to the drug effect and adverse reaction, so that the monitoring of the drug concentration of the MPA in vivo has important significance in clinical medication. The current common methods for detecting mycophenolic acid are as follows: ultraviolet spectrophotometry, homogeneous immunoassay, high performance liquid chromatography, liquid chromatography-mass spectrometry, etc.
The stable isotope internal standard mass spectrometry is a method for calculating the content of the element in a sample by using concentrated stable isotopes with known mass and abundance as internal standard substances to prepare internal standard liquid with a certain concentration, quantitatively adding the internal standard liquid into the sample, uniformly mixing, and measuring the change of the isotope abundance before and after mixing by using a mass spectrometer. The method is a method with high accuracy and precision because the content is determined according to the measurement of the isotope ratio, and the measurement of the ratio is less influenced by matrix effect and instrument condition change.
In current analytical techniques for the detection of mycophenolic acid, internal standards are generally classified into two types, namely structural analog internal standards (e.g., indomethacin, naproxen) and isotopic internal standards (mycophenolic acid-D3). The difference between the isotope internal standard and the object to be detected in ionization efficiency and recovery rate is smaller, and the method using the isotope as the internal standard is superior to the method using a structural analogue as the internal standard in precision, accuracy and stability.
Patent document [ application No. 200810202401.X ] invents a method for simultaneously measuring mycophenolate mofetil, mycophenolic acid and metabolites thereof in human urine, and a test strip invented in patent document [ publication No. CN 110376386A ], although the operation is convenient, the accuracy of the test strip needs to be further verified, and the sensitivity is lower than that of a mass spectrometry method. Patent document [ CN110554123A ] a method, a kit and an application for rapidly detecting an immunosuppressant in whole blood "uses 10ng/mL mycophenolic acid isotope internal standard in mass spectrometry detection, but the structure or other usable concentrations of the internal standard are not specifically described. No mass spectrometry method for determining the content of mycophenolic acid in various biological samples by using mycophenolic acid-D3 (the concentration range is 2.5 mu g/mL-10 mu g/mL) is reported at present.
Disclosure of Invention
One of the objectives of the present invention is to provide a mass spectrometry detection reagent and a method for using the same, which can accurately and stably monitor the concentration of mycophenolic acid in various biological samples such as blood, urine, and tissues, by using mycophenolic acid-D3 with the optimum concentration and operation as an internal standard to measure the content of mycophenolic acid in the biological samples, in view of the shortcomings of the prior art.
The technical scheme adopted by the invention for solving the technical problem is as follows:
1. a mass spectrum detection reagent for measuring the content of mycophenolic acid in a biological sample by using mycophenolic acid-D3 as an internal standard and a using method thereof are characterized in that: the invention relates to a mass spectrometry detection reagent containing mycophenolic acid-D3 and a using method thereof, which are used for detecting the content of mycophenolic acid in a biological sample.
2. Furthermore, the mycophenolic acid-D3 is stable isotope (deuterium) labeled mycophenolic acid, has a higher molecular mass number than mycophenolic acid, and can be distinguished from the mycophenolic acid in mass spectrometry detection. Dissolving mycophenolic acid-D3 in organic solution such as methanol, ethanol, acetonitrile and the like to prepare mycophenolic acid-D3 internal standard stock solution with the concentration range of 200 mu g/mL-1 mg/mL, and diluting to 2.5 mu g/mL-10 mu g/mL before use.
3. Further, preparing the mycophenolic acid standard substance into 6-8 concentration gradient solutions (the concentration range is 0.10-40.00 mu g/mL) for drawing a standard curve. And (3) taking mycophenolic acid-D3 as an internal standard, diluting a sample to be detected according to a certain proportion, and detecting by a mass spectrometry method.
4. Further, the standard curve is a regression equation Y ═ aX + b obtained by performing linear regression analysis on the mycophenolic acid labeled concentration (X) by using the ratio (Y) of the actually measured peak area of the mycophenolic acid calibrator to the peak area of the internal standard mycophenolic acid-D3 and adopting a weighted least square method, wherein a is the slope and b is the intercept.
5. Further, a sample is collected from the living body after administration of mycophenolate mofetil, and a pretreatment of the sample is performed. Biological samples include body fluids, cells or tissues of human and animal origin, wherein the body fluids include whole blood, plasma or serum, urine, saliva, interstitial fluid (cerebrospinal fluid, lymph fluid) and the like. Acetonitrile is adopted to precipitate protein before sample pretreatment.
6. Further, substituting the detection signal (the ratio of the chromatographic peak areas of the mycophenolic acid and the mycophenolic acid-D3 in the sample to be detected) into a standard curve equation to calculate the mycophenolic acid content.
The invention has the advantages that:
1. stable isotope mycophenolic acid-D3 is used as an internal standard, the extraction efficiency and absolute matrix effect of the compound are very close to those of mycophenolic acid, and the influence of the effect of sample processing and detection processes on the result can be reduced to the greatest extent.
2. The correlation coefficient r of the standard curve is more than 0.99 during multiple verification, the variation coefficient of the detection precision is less than 10%, the accuracy is more than 90%, and the method is stable.
3. Adopts a direct acetonitrile protein precipitation method. The method has simple operation, low cost and short time consumption; the mobile phase contains 0.1% formic acid, which is beneficial to improving the ionization efficiency of the mycophenolic acid, thereby improving the sensitivity of the method.
Detailed Description
In order to make the technical means, characteristics, achievement purposes and effects of the invention easy to understand, two biological samples of plasma and urine are taken as examples, and the specific implementation steps of the invention are further described.
Example 1 plasma sample
Firstly, reagent preparation:
1. mycophenolic acid control stock solution: accurately weighing 10.0mg of mycophenolic acid standard substance, placing the mycophenolic acid standard substance into a 10mL volumetric flask, adding methanol to dissolve and dilute the mycophenolic acid standard substance to a scale, wherein the concentration is 1 mg/mL; subpackaging, and freezing at-80 deg.C.
2. Mycophenolic acid-D3 internal standard solution: precisely weighing 5.0mg of mycophenolic acid-D3, placing the mycophenolic acid-D3 into a 10mL volumetric flask, adding methanol to dissolve and dilute the mycophenolic acid-D3 to a scale mark, and obtaining a stock solution with the concentration of 500 mu g/mL. Then, 500. mu.L of the solution was aspirated into a 50mL volumetric flask, and the volume of methanol was fixed to obtain 5. mu.g/mL of a working solution. Subpackaging and freezing at-80 deg.C.
3. Calibrator (standard curve reagent):
20 mu L of mycophenolic acid reference substance solution is sucked, 480 mu L of blank plasma is added to prepare 40 mu g/mL solution A.
A150. mu.L of the solution was aspirated, and 150. mu.L of blank plasma was added to prepare a solution B having a concentration of 20. mu.g/mL.
150. mu.L of B was aspirated, and 150. mu.L of blank plasma was added to prepare a solution C having a concentration of 10. mu.g/mL.
150. mu.L of C was aspirated, and 150. mu.L of blank plasma was added to prepare solution D having a concentration of 5. mu.g/mL.
150. mu.L of the resulting solution was pipetted, and 150. mu.L of blank plasma was added to prepare a solution E having a concentration of 2.5. mu.g/mL.
After 150. mu.L of E was aspirated, 150. mu.L of blank plasma was added to prepare a solution F having a concentration of 1.25. mu.g/mL.
F150. mu.L was aspirated, and 150. mu.L of blank plasma was added to prepare a solution G having a concentration of 0.625. mu.g/mL.
Draw 150. mu.L of G, add 150. mu.L of blank plasma, and formulate solution H at a concentration of 0.3125. mu.g/mL.
4. Quality control product: the stock solution of the mycophenolic acid reference substance is diluted by blank plasma to prepare three concentrations of high concentration, medium concentration and low concentration, which are respectively 13.33 mu g/mL, 4.44 mu g/mL and 1.48 mu g/mL, and each bottle is separately filled with 1.0 mL. The components are freeze-dried and stored at the bottom of a measuring bottle.
5. Mobile phase a (2 mmol/L aqueous ammonium acetate solution with 0.1% formic acid): precisely weighing 200 mu L of formic acid and 30.9mg of ammonium acetate in 200mL of ultrapure water, uniformly mixing, and carrying out ultrasonic treatment for 10 min.
6. Mobile phase B (acetonitrile with 0.1% formic acid): precisely measuring 900 mu L of formic acid in 900mL of acetonitrile, uniformly mixing, and carrying out ultrasonic treatment for 10 min.
Second, sample preparation
1. Collecting samples: plasma samples were collected according to the limited sampling method and concentrations were recorded as C0 (pre-dose), C0.5 (0.5 h post-dose), C2 (2 h post-dose) based on the sampling time points. And storing at 2-8 ℃ for standby testing.
2. Sample pretreatment:
(1) accurately transferring 20 μ L of the plasma sample into a 1.5mL EP tube, adding 20 μ L of the internal standard working solution, and mixing well.
(2) Acetonitrile 400. mu.L was added.
(3) Vortex and shake for 5min, 12000rpm, centrifuge for 10min at 4 ℃.
(4) 200 μ L of supernatant was taken for mass spectrometric detection.
Third, detection analysis
1. The applicable instrument: acquity UPLC ultra high performance liquid chromatograph, Quattro Premier XE triple quadrupole mass spectrometer.
2. Chromatographic conditions are as follows: the chromatographic column adopts Waters BEH C18(50 × 2.1.1 mm, 1.8 μm), mobile phase A is ammonium acetate aqueous solution containing 0.1% formic acid, B is acetonitrile containing 0.1% formic acid, column temperature is 40 deg.C, sample injection amount is 2 μ L, flow rate is 0.2ml min-1The gradient elution parameters are set forth in table 1.
TABLE 1 gradient elution conditions
3. Mass spectrum conditions: in positive ion detection mode (+ ESI); capillary voltage: 3.0 kV; taper hole voltage: 12V; temperature of the taper hole: 120 ℃; ion source temperature: 350 ℃; desolventizing gas (N)2) Flow rate: 800 L.h-1(ii) a Taper hole back-blowing airflow speed of 10 L.h-1(ii) a Adopting an MRM scanning mode; monitoring ion pairs: mycophenolic acid 321.2-207.2, mycophenolic acid-D3324.2-210.2.
4. And (3) determination: and (3) preprocessing a calibrator, a quality control product and a sample to be detected, then quantitatively analyzing 200 mu L of supernate, and recording chromatographic peak areas of different ion channels.
5. Quality control: for each 1 analysis batch, 1 standard curve (1 for each calibrator sample with different concentration values) and 2 quality control samples (2 selected from high, medium and low concentrations). The deviation of the measurement result of the quality control sample is less than 15%, and the result of the quality control sample of 1/3 is allowed to exceed the limit at most, but can not be present in the same concentration of the quality control sample. If the testing result of the quality control sample does not meet the requirement, the testing result of the analysis batch sample is invalidated and is detected again.
6. Calculation of results
(1) Drawing a standard curve: the concentrations of 8 calibrators with different marked concentrations are used as abscissa (X), and the actual measurement of 8 calibrators samples is usedThe ratio of the peak area to the peak area of mycophenolic acid-D3 is plotted on the ordinate (Y) to obtain a standard curve. Using weighting (1/x)2) The least squares method performs linear regression. Fitting a linear regression equation: y ═ aX + b, where a is the slope and b is the intercept.
(2) And (3) calculating the recovery rate: and substituting the ratio of the measured peak area of the quality control product to the peak area of the mycophenolic acid-D3 into the standard curve equation to calculate the actually measured concentration of the quality control sample. According to the formula "recovery (%) — measured concentration/labeled concentration × 100", the result should be in the range of 100 ± 15%.
(3) Sample result calculation: substituting the peak area of the sample into a standard curve equation, and calculating the concentration of the mycophenolic acid drug in the sample.
Specific example 2: urine sample
Firstly, reagent preparation: (the procedure of example 1 was repeated except for the calibrator and the quality controller)
Calibrator (standard curve reagent):
absorbing 15 mu L of mycophenolic acid reference substance solution, adding 485 mu L of blank urine, and preparing into 30 mu g/mL solution A.
A150. mu.L of the solution A was aspirated, and 150. mu.L of blank urine was added to prepare a solution B having a concentration of 15. mu.g/mL.
Aspirate B100. mu.L and add blank urine 200. mu.L to prepare solution C with a concentration of 5. mu.g/mL.
Aspirate C60. mu.L and add 240. mu.L of blank urine to prepare solution D with a concentration of 1. mu.g/mL.
150 μ L of D was aspirated, and 150 μ L of blank urine was added to prepare a solution E having a concentration of 0.5 μ g/mL.
Aspirate E60. mu.L and add 240. mu.L of blank urine to prepare a solution F with a concentration of 0.1. mu.g/mL.
F150. mu.L was aspirated, and 150. mu.L of blank plasma was added to prepare a solution G having a concentration of 0.05. mu.g/mL.
Quality control product: adding blank urine into mycophenolic acid to prepare three concentrations of high concentration, medium concentration and low concentration, which are respectively 0.5 mu g/mL, 5.0 mu g/mL and 30 mu g/mL, and storing at-20 ℃.
Second, sample preparation
1. Collecting samples: taking a middle section urine sample within 0.5h before taking the medicine, and storing and testing at 2-8 ℃.
2. Sample pretreatment:
(1) accurately transferring 20 mu L of urine sample into a 1.5mL EP tube, adding 100 mu L of methanol solution for urine sample dilution, centrifuging, taking 80 mu L of supernatant, adding 20 mu L of internal standard working solution, and properly mixing.
(3) Acetonitrile 400. mu.L was added.
(4) Vortex and shake for 5min, centrifuge at 12000rpm for 10 min.
(5) 200 μ L of supernatant was taken for mass spectrometric detection.
Third, detection analysis
1. The applicable instrument: acquity UPLC ultra high performance liquid chromatograph, Quattro Premier XE triple quadrupole mass spectrometer.
2. Chromatographic conditions are as follows: the chromatographic column adopts Waters BEH C18(50 × 2.1.1 mm, 1.8 μm), mobile phase A of 0.1% formic acid in ammonium formate water, phase B of methanol, column temperature of 40 deg.C, sample injection amount of 2 μ L, and flow rate of 0.2 ml/min-1Gradient elution parameter settings:
TABLE 2 gradient elution conditions
3. Conditions of Mass Spectrometry
In positive ion detection mode (+ ESI); capillary voltage: 3.0 kV; taper hole voltage: 12V; temperature of the taper hole: 120 ℃; ion source temperature: 350 ℃; flow rate of desolventizing gas (N2): 800 L.h-1(ii) a Taper hole blowback air flow rate: 10 L.h-1(ii) a Adopting an MRM scanning mode; monitoring ion pairs: mycophenolic acid 321.2-207.2, mycophenolic acid-D3324.2-210.2.
4. Measurement of
And (3) after sample pretreatment is carried out on the calibrator, the quality control product and the sample to be detected, taking 200 mu L of supernate for quantitative analysis, and recording the chromatographic peak areas of different ion channels.
5. Quality control
For each 1 analysis batch, 1 standard curve (1 for each of 7 calibrators of different concentration values) and 2 quality control samples (2 selected from high, medium and low concentrations). The deviation of the measurement result of the quality control sample is less than 15%, and the result of the quality control sample of 1/3 is allowed to exceed the limit at most, but can not be present in the same concentration of the quality control sample. If the testing result of the quality control sample does not meet the requirement, the testing result of the analysis batch sample is invalidated and is detected again.
6. Calculation of results
(1) Drawing a standard curve: and (5) drawing a standard curve by taking the standard concentration of the calibrator as an abscissa (X) and taking the ratio of the actually measured peak area of the calibrator sample to the peak area of the mycophenolic acid-D3 as an ordinate (Y). Using weighting (1/x)2) The least squares method performs linear regression. Fitting a linear regression equation: y ═ aX + b, where a is the slope and b is the intercept, the correlation coefficient (r) should be>0.9900. When the concentration of mycophenolic acid in the urine sample is within the range of 0.1-30 mug/mL, a good linear relation exists between the detection signal and the concentration, and the concentration can be calculated through a standard curve.
(2) And (3) calculating the recovery rate: and substituting the ratio of the measured peak area of the quality control product to the peak area of the mycophenolic acid-D3 into the standard curve equation to calculate the actually measured concentration of the quality control sample. The recovery rate is calculated according to the formula "measured concentration (%)/" labeled concentration × 100 "and should be within a range of 100 ± 15%.
(3) Sample result calculation:
substituting the peak area of the sample into a standard curve equation, and calculating the concentration (mu g/mL) of the mycophenolic acid in the sample.
Summary of the invention
Under the condition of the method, the correlation coefficient of the standard curve of the mycophenolic acid and the recovery rate of the quality control product both accord with the regulations, and the accuracy of the result of the sample measured by the method can be ensured.
The foregoing shows and describes the general principles, essential features, and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are given by way of illustration of the principles of the present invention, and that various changes and modifications may be made without departing from the spirit and scope of the invention as defined by the appended claims.
Claims (6)
1. A mass spectrum detection reagent for measuring the content of mycophenolic acid in a biological sample by using mycophenolic acid-D3 as an internal standard substance and a using method thereof are characterized in that: the invention relates to a mass spectrometry detection reagent containing mycophenolic acid-D3 and a using method thereof, which are used for detecting the content of mycophenolic acid in a biological sample.
2. The correlation reagent according to claim 1, characterized in that: the mycophenolic acid D3 is stable isotope (deuterium) labeled mycophenolic acid, has a higher molecular mass number than mycophenolic acid, and can be distinguished from the mycophenolic acid in mass spectrum detection.
3. The correlation reagent according to claim 1, characterized in that: the biological sample includes body fluid, cells or tissues of human and animal origin, wherein the body fluid includes whole blood, plasma or serum, urine, saliva, interstitial fluid (cerebrospinal fluid, lymph fluid) and the like.
4. The correlation reagent according to claim 1, characterized in that: the detected substances are Mycophenolic Acid, also called Mycophenolic Acid, Mycophenolic Acid and MPA, and are active metabolites of mycophenolate mofetil in vivo. Mycophenolate mofetil is a common immunosuppressive agent for organ transplantation and is widely applied to organ transplantation patients, and the reagent and the method are mainly used for measuring the mycophenolic acid content in organisms after the mycophenolate mofetil is taken.
5. The method of using the reagent according to claim 1, wherein: preparing a reagent with a certain concentration by taking mycophenolic acid-D3 as an internal standard, sucking and adding the reagent into a sample to be detected according to a certain proportion, processing the sample, and detecting the content of mycophenolic acid by a mass spectrometry method. The solvent used for preparing the mycophenolic acid-D3 internal standard solution can be organic solution such as methanol, ethanol, acetonitrile and the like, the concentration range of the stock solution is 200 mu g/mL-1 mg/mL, and the use concentration range is 2.5 mu g/mL-10 mu g/mL.
6. The method of claim 1, wherein when the concentration of mycophenolic acid is within the range of 0.1-40 μ g/mL, the linear relationship (r >0.99) between the detection signal (the ratio of the chromatographic peak area of mycophenolic acid to the chromatographic peak area of mycophenolic acid D3) and the concentration is relatively good, and the concentration of mycophenolic acid in the sample to be detected can be calculated by a standard curve.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112213417A (en) * | 2020-09-16 | 2021-01-12 | 苏州药明泽康生物科技有限公司 | Kit and method for detecting concentration of mycophenolic acid medicine in dried blood spots |
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| US20080318322A1 (en) * | 2006-01-27 | 2008-12-25 | Fatemeh Akhlaghi | Analysis of mycophenolic acid in saliva using liquid chromatography tandem mass spectrometry |
| CN110554123A (en) * | 2019-09-11 | 2019-12-10 | 深圳华大临床检验中心 | Method and kit for rapidly detecting immunosuppressant in whole blood and application of kit |
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2020
- 2020-06-09 CN CN202010508310.XA patent/CN111579690A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080318322A1 (en) * | 2006-01-27 | 2008-12-25 | Fatemeh Akhlaghi | Analysis of mycophenolic acid in saliva using liquid chromatography tandem mass spectrometry |
| CN110554123A (en) * | 2019-09-11 | 2019-12-10 | 深圳华大临床检验中心 | Method and kit for rapidly detecting immunosuppressant in whole blood and application of kit |
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| Title |
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| ARMIN BUCHWALD 等: "Validation of an LC-MS/MS method to determine five immunosuppressants with deuterated internal standards including MPA", 《BMC CLINICAL PHARMACOLOGY》 * |
| 朱顺海 等: "高效液相色谱法同时测定霉酚酸酯及霉酚酸的血药浓度", 《上海医药》 * |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112213417A (en) * | 2020-09-16 | 2021-01-12 | 苏州药明泽康生物科技有限公司 | Kit and method for detecting concentration of mycophenolic acid medicine in dried blood spots |
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