CN110715998A - Online solid phase extraction liquid chromatography for detecting linezolid content in blood - Google Patents
Online solid phase extraction liquid chromatography for detecting linezolid content in blood Download PDFInfo
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- CN110715998A CN110715998A CN201910711053.7A CN201910711053A CN110715998A CN 110715998 A CN110715998 A CN 110715998A CN 201910711053 A CN201910711053 A CN 201910711053A CN 110715998 A CN110715998 A CN 110715998A
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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
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
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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
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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
- G01N2030/062—Preparation extracting sample from raw material
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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
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
- G01N2030/8809—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample
- G01N2030/8813—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample biological materials
- G01N2030/8822—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample biological materials involving blood
Abstract
The invention belongs to the field of medical inspection, relates to a method for measuring the content of in-vivo antibacterial drugs, and particularly relates to an online solid-phase extraction liquid chromatography method for detecting the content of linezolid in blood. The invention relates to an online solid-phase extraction liquid chromatography for detecting the linezolid content in blood, which is characterized in that after a blood sample to be detected is pretreated, a high performance liquid chromatograph is used for determining the linezolid content by adopting a standard curve method.
Description
Technical Field
The invention belongs to the field of medical inspection, relates to a method for measuring the content of an in-vivo antibacterial drug, and particularly relates to an online solid-phase extraction liquid chromatography method for detecting the content of linezolid in blood.
Background
Linezolid is a synthetic antibiotic of the oxazolidinone type and is useful for the treatment of infections caused by aerobic gram-positive bacteria. Linezolid is a bacterial protein synthesis inhibitor, acts on bacterial 50S ribosomal subunit, inhibits mRNA from connecting with ribosome, and prevents the formation of 70S initiation complex, thereby inhibiting the synthesis of bacterial protein. Linezolid (LNZA) has the molecular formula C16H20FN3O4The effective blood concentration of linezolid is 1.0-4.0mg/L, and when the blood concentration is more than 4.0mg/L, toxic and side effects are enhanced. Adverse reactions are common, nausea, anemia, and thrombocytopenia. Due to the narrow therapeutic window of LNZA, metabolic processes exist in vivoThe large individual difference ensures that the monitoring of the blood concentration is an important reference for adjusting the dosage and reducing the adverse reaction, and has great significance in clinical medication.
At present, a plurality of commonly used methods for measuring the blood concentration of linezolid exist, but at present, the problems of complex pretreatment, high cost, high requirements on experimenters and environment, long analysis time and the like still exist.
In conclusion, the development and verification of the rapid, sensitive and selective liquid chromatography for determining the linezolid content in human plasma have important analytical significance.
Disclosure of Invention
The invention aims to provide an online solid-phase extraction liquid chromatography for detecting the content of linezolid in blood aiming at the current situation of the prior art.
The technical scheme adopted by the invention for solving the technical problem is as follows:
an online solid phase extraction liquid chromatography method for detecting the linezolid content in blood is characterized by comprising the following steps:
(1) pretreatment of plasma samples: taking a sample to be detected, and adding a protein precipitator for precipitation;
(2) drawing a standard curve, namely adding 20uL of standard working solution into 1ml of blank plasma, uniformly mixing the blank plasma and the blank plasma into standard solutions with 6 concentrations, respectively adding a protein precipitator into the obtained standard solutions for precipitation, centrifuging the solutions at 9000 and 15000rpm for 10 to 15min, respectively taking supernate, detecting the supernate by using a high performance liquid chromatograph and a DAD detector to obtain a linezolid spectrogram in the standard solutions, taking the peak area of linezolid as the ordinate y of a standard curve graph, taking the concentration of linezolid in the standard working solution as the abscissa x of the standard curve graph, carrying out linear regression on data, fitting to obtain a standard curve equation of y a x + b, and obtaining weight coefficients a and b and related coefficients R2(ii) a The standard curve is drawn for at least three times by using three different batches of standard working solution; the standard working solution is a solution containing linezolid;
(3) centrifuging the detected blood, namely centrifuging at least 2ml of the detected blood at the centrifugation speed of 3500-4500rpm for 10-15min to obtain supernatant, and storing the supernatant at-20 ℃ for later use;
(4) and (3) detection of a sample to be detected:
s1, heating the mixture in a water bath (37 ℃), and re-melting the supernatant obtained in the step (3);
s2, using a liquid transfer gun to transfer the supernatant 800-1000uL after the re-melting in the step S1, and performing pretreatment according to the step (1) and centrifuging to obtain the supernatant which is the sample to be detected;
and S3, moving the sample to be detected 600-800uL in the step (c), detecting the sample to be detected by using a high performance liquid chromatograph and a DAD detector to obtain a linezolid chromatogram of the sample to be detected, substituting the linezolid peak area y in the chromatogram into the standard curve equation y a x + b in the step (2), and calculating to obtain the concentration of linezolid in the sample to be detected.
2. The liquid chromatography method of claim 1, wherein: the protein precipitant is acetonitrile.
Further, the standard working solution in the step (2) is linezolid solution with the concentration of 0.3, 0.9, 2.0, 5.0, 9.0 and 12.0 μ g/mL.
Further, the high performance liquid chromatograph in the step (2) comprises a sample injection module, a liquid phase pump module, a column temperature module, a detector module, an extraction pump, a liquid supplement pump, a six-way valve, an analysis column and an SPE column.
Furthermore, the mobile phase of the SPE column is 0.01-0.02% phosphoric acid water solution, the flow rate is 0.4-0.5mL/min, and the SPE column adopts a backflushing mode.
Further, the mobile phase of the analytical column is a 10% organic phase and a 90% aqueous phase, the organic phase is acetonitrile, and the aqueous phase is a 0.01-0.02% phosphoric acid aqueous solution; the flow rate is 1-1.2mL/min, and the analytical column adopts a gradient elution mode.
Further, the detection wavelength of the DAD detector in the step (2) is 254 nm.
The invention has the advantages that: according to the online solid-phase extraction liquid phase analysis method for detecting the drug concentration of linezolid in blood, plasma is directly injected after protein precipitation, so that the personnel operation is reduced, the accuracy of a quantitative result is improved, the analysis time is greatly shortened, the detection process is simple, convenient and quick, the experiment cost is reduced, the plasma concentration of linezolid in a patient body can be monitored in clinical treatment, and an experiment basis is provided for personalized administration of linezolid and reduction of toxic and side effects.
Drawings
FIG. 1 is a schematic diagram of the working flow of on-line solid phase extraction analysis.
FIG. 2 is a chromatogram of linezolid in a standard solution according to the present invention;
FIG. 3 is a chromatogram of linezolid in a spiked plasma sample according to the invention.
Detailed Description
In order to make the technical means, the original characteristics, the achieved purposes and the effects of the invention easy to understand, the invention is further described with reference to the figures and the specific embodiments.
Example 1
Pretreatment of plasma samples: taking a sample to be detected, and adding a protein precipitator for precipitation.
Secondly, drawing a standard curve, firstly, using a pipette to place 20uL of standard working solution into a 10ml centrifuge tube, adding blank plasma to 1mL, mixing to obtain standard solutions with 6 concentrations, adding protein precipitant into the standard solutions respectively for precipitation, centrifuging at 15000rpm for 10-15min, respectively taking 500uL of the supernatant, detecting the supernatant by using a high performance liquid chromatograph and a DAD detector to obtain a linezolid spectrogram in the standard solution, taking the linezolid peak area as the ordinate y of a standard curve graph, taking the concentration of linezolid in the standard working solution as the abscissa x of the standard curve graph, performing linear regression on the data, fitting to obtain a standard curve equation of y ═ a × x + b, and obtaining weight coefficients a and b and a correlation coefficient R2. The standard curve is plotted at least three times with three different batches of standard working fluid. The standard working solution is a solution containing linezolid.
Preparing a standard working solution:
(a) accurately weighing 10mg of linezolid standard substance, placing the 10mg standard substance in a 1mL volumetric flask, dissolving the linezolid standard substance with methanol and determining the volume of the linezolid standard substance to obtain a standard stock solution A, wherein the concentration of linezolid is 10mg/mL, diluting the standard stock solution A with blood plasma, respectively preparing standard working solutions with various concentrations in the range of 15-600 mu g/mL of linezolid, and storing the standard working solutions at-80 ℃;
(III) centrifugation of test blood
Centrifuging at least 2ml of blood to be detected at a centrifugal speed of 3500rpm for 10min to obtain supernatant, and freezing the supernatant at-20 deg.C for storage until the supernatant is ready for analysis;
(IV) treatment of the sample to be tested
(b) Heating with water bath (37 deg.C), and re-melting the frozen plasma of step (III).
(c) And (c) transferring 1000uL of the plasma under the item (b) into a 10mL centrifuge tube by using a pipette gun, pretreating according to the step (I), and centrifuging to obtain a supernatant, namely the sample to be detected.
(IV) detection of sample to be tested
And (3) transferring 800uL of the sample to be detected in the step (c), detecting the sample to be detected by using a high performance liquid chromatograph and a DAD detector to obtain a linezolid chromatogram of the sample to be detected, substituting the linezolid peak area y in the chromatogram into the standard curve equation y ═ a x + b in the step (two), and calculating to obtain the concentration of linezolid in the sample to be detected.
In the step (II), six standard working solutions with different concentrations are used, and the six standard working solutions with different concentrations are linezolid solutions with concentrations of 0.3, 0.9, 2.0, 5.0, 9.0 and 12.0 mu g/mL respectively;
as shown in fig. 1, the conventional high performance liquid chromatograph includes: advance kind module, liquid phase pump module, column temperature module and detector module, high performance liquid chromatograph still includes: the device comprises an extraction pump, a liquid supplementing pump, a six-way valve and an SPE column, wherein the SPE column is SPENJH 301002; the SPE column mobile phase of the on-line solid phase extractor is 0.01 percent phosphoric acid water solution, and the flow rate is 0.4 mL/min; the mobile phase of the fluid infusion pump is pure water, and the flow rate is 1.0 mL/min; the SPE column uses a backflush mode.
Analytical column the mobile phase contained a 10:90 ratio of organic phases: the water phase, wherein the organic phase is acetonitrile, the water phase is an aqueous solution containing 0.01% phosphoric acid, the flow rate of an analytical chromatographic column is 1.2mL/min, and the analytical chromatographic column adopts an isocratic elution mode;
the DAD detector is Thermo DAD-3000, and the detection wavelength is 254 nm.
The technical method in this example is demonstrated as follows:
first, the linear relationship and quantitative limits of the method
Adding 980 mu L of blank plasma into 20 mu L of the prepared linezolid standard working solution with each concentration (15-600 mu g/mL), uniformly mixing, diluting, injecting a sample, measuring according to the measuring conditions of the embodiment from low to high according to the concentration, and drawing by using a quantitative chromatographic peak area-concentration to obtain a standard curve, wherein the linear range and the quantitative limit of the linezolid are as follows:
(1) limit of detection (LOD): 0.05 mg/L.
(2) Limit of quantitation (LOQ): 0.3 mg/L.
(3) Linear range:
linezolid is in the range of 0.3mg/L to 12mg/L, the linearity is good, and the correlation coefficient R2>0.99。
Second, the recovery rate and precision of the method
The linezolid standard working solution was prepared into high, medium and low 3 concentrations for sample recovery rate test and precision test, the test was performed according to the method of this example, and the analysis and determination were repeated for 3 batches, with the recovery rate and precision being shown in table 1. The average recovery rate of the compound is 94.5-102.3% within the range of 3 addition levels of low, medium and high, the relative standard deviation is 1.25-1.52%, and the standard addition recovery rate and the precision of the linagliclamide are shown in a table 1.
TABLE 1 Linezolid recovery and precision with standard addition
Thirdly, stability of the solution
The prepared precision sample of linezolid was taken and the stability of the sample solution was determined according to the method of this example. The results of the experiment show that the sample is stable within 7 hours.
By combining the verification tests, the technical indexes of the detection limit, the recovery rate, the precision, the stability and the like of the embodiment meet the requirements, and the method for detecting the concentration of the linezolid in blood has the advantages of good reproducibility, high sample recovery rate and improvement on the accuracy of the detection result.
The chromatogram of linezolid in the standard solution is shown in figure 2, the chromatogram of linezolid in the serum sample is shown in figure 3, the retention time of linezolid is 11.15min, and as can be seen from figures 2 and 3, the method has the advantages of accurate identification of the target compound, short analysis time, small interference and strong specificity.
The foregoing illustrates and describes the principles, general features, and advantages of the present 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. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (7)
1. An online solid phase extraction liquid chromatography method for detecting the linezolid content in blood is characterized by comprising the following steps:
(1) pretreatment of plasma samples: taking a sample to be detected, and adding a protein precipitator for precipitation;
(2) drawing a standard curve, namely adding blank plasma into 20uL of standard working solution to 1ml, uniformly mixing the blank plasma and the standard solution to form standard solutions with 6 concentrations, respectively adding a protein precipitator into the obtained standard solutions for precipitation, centrifuging the standard solutions at 9000-15000rpm for 10-15min, respectively taking supernate, detecting the supernate by using a high performance liquid chromatograph and a DAD detector to obtain a linezolid spectrogram in the standard solution, and using linezolidThe peak area of the standard working solution is used as the ordinate y of the standard curve graph, the concentration of linezolid in the standard working solution is used as the abscissa x of the standard curve graph, the data is subjected to linear regression, a standard curve equation is obtained by fitting, and weight coefficients a and b and a correlation coefficient R are obtained2(ii) a The standard curve is drawn for at least three times by using three different batches of standard working solution; the standard working solution is a solution containing linezolid;
(3) centrifuging the detected blood, namely centrifuging at least 2ml of the detected blood at the centrifugation speed of 3500-4500rpm for 10-15min to obtain supernatant, and storing the supernatant at-20 ℃ for later use;
(4) and (3) detection of a sample to be detected:
s1, heating the mixture in a water bath (37 ℃), and re-melting the supernatant obtained in the step (3);
s2, using a liquid transfer gun to transfer the supernatant 800-1000uL after the re-melting in the step S1, and performing pretreatment according to the step (1) and centrifuging to obtain the supernatant which is the sample to be detected;
and S3, transferring the sample to be detected 600-800uL in the step (c), detecting the sample to be detected by using a high performance liquid chromatograph and a DAD detector to obtain a linezolid chromatogram of the sample to be detected, substituting the linezolid peak area y in the chromatogram into the standard curve equation y ═ a x + b in the step (2), and calculating to obtain the concentration of linezolid in the sample to be detected.
2. The liquid chromatography method of claim 1, wherein: the protein precipitant is acetonitrile.
3. The liquid chromatography method of claim 1, wherein: the standard working solution in the step (2) is linezolid solution with the concentration of 0.3, 0.9, 2.0, 5.0, 9.0 and 12.0 mu g/mL.
4. The liquid chromatography method of claim 1, wherein: the high performance liquid chromatograph in the step (2) comprises a sample injection module, a liquid phase pump module, a column temperature module and a detector module, and further comprises an extraction pump, a liquid supplement pump, a six-way valve, an analysis column and an SPE column.
5. A liquid chromatography method according to claim 4, characterized in that: the mobile phase of the SPE column is 0.01-0.02% phosphoric acid water solution, the flow rate is 0.4-0.5mL/min, and the SPE column adopts a backflushing mode.
6. The liquid chromatography method of claim 4, wherein: the mobile phase of the analytical column is a 10% organic phase and a 90% aqueous phase, the organic phase is acetonitrile, and the aqueous phase is a 0.01-0.02% phosphoric acid aqueous solution; the flow rate is 1-1.2mL/min, and the analytical column adopts a gradient elution mode.
7. A liquid chromatography method as claimed in claim 1, wherein: the detection wavelength of the DAD detector in the step (2) is 254 nm.
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CN112986459A (en) * | 2021-04-15 | 2021-06-18 | 安徽万邦医药科技股份有限公司 | LC-MS/MS detection method for linezolid in human plasma |
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