CN111337607A - On-line solid phase extraction liquid chromatography for detecting kanamycin content in blood - Google Patents
On-line solid phase extraction liquid chromatography for detecting kanamycin content in blood Download PDFInfo
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- CN111337607A CN111337607A CN201910711065.XA CN201910711065A CN111337607A CN 111337607 A CN111337607 A CN 111337607A CN 201910711065 A CN201910711065 A CN 201910711065A CN 111337607 A CN111337607 A CN 111337607A
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- 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
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- 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
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Abstract
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 for detecting the content of kanamycin in blood. The invention relates to an online solid-phase extraction liquid chromatography for detecting kanamycin 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 kanamycin 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 for detecting the content of kanamycin in blood.
Background
Kanamycin is a protein biosynthesis inhibitor, and causes misreading of mRNA codes by binding to 30S ribosome. If an enzyme that destroys kanamycin is produced in the bacteria, it becomes a resistant strain. Kanamycin-resistant plasmids are frequently used as selection genes or marker genes in molecular cloning. When the blood concentration of kanamycin is more than 10mg/L, toxic and side effects are enhanced. Causing temporary 9 impairment of cranial nerve function (manifested as post-1/3 taste loss), paraoral and other sensory abnormalities, headaches, restlessness, tachycardia, acute brain syndrome with hysteria and abnormal vision. Because the VCMC has a narrow therapeutic window and large individual difference in the metabolic process in vivo, the monitoring of the blood concentration is an important reference for adjusting the dosage and reducing adverse reactions, and has great significance in clinical medication.
At present, a plurality of commonly used methods for measuring the blood concentration of kanamycin exist, but the problems of complex pretreatment, high cost, high requirements on experimenters and environment, long analysis time and the like still exist at present.
Disclosure of Invention
The invention aims to provide an online solid-phase extraction liquid chromatography for detecting the kanamycin content 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 on-line solid phase extraction liquid chromatography for detecting the kanamycin 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 taking 20uL standard working solution, adding blank plasma to 1ml, uniformly mixing to obtain standard solutions with 6 concentrations, respectively adding a protein precipitator into the obtained standard solutions for precipitation, centrifuging 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 kanamycin spectrogram in the standard solutions, taking the peak area of kanamycin as the ordinate y of a standard curve graph, taking the concentration of kanamycin in the standard working solution as the abscissa x of the standard curve graph, performing linear regression on 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(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 kanamycin;
(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, removing the sample to be detected 600 and 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 kanamycin chromatogram of the sample to be detected, substituting the kanamycin 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 kanamycin in the sample to be detected.
The protein precipitant is acetonitrile.
Further, the standard working solutions in the step (2) are kanamycin solutions with the concentration of 0.5, 2.5, 5.5, 9.0, 13.0 and 18.0 mu 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 0.03-0.05% 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 30% organic phase and a 70% aqueous phase, the organic phase is acetonitrile, and the aqueous phase is a 0.03-0.05% 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 218 nm.
The invention has the advantages that: according to the on-line solid-phase extraction liquid phase analysis method for detecting the concentration of the kanamycin in blood, plasma is subjected to protein precipitation and then directly subjected to sample injection, so that the operation of personnel 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 monitoring on the kanamycin blood concentration in a patient body in clinical treatment is facilitated, and the experiment basis is provided for individualized administration of kanamycin and reduction of toxic and side reactions.
Drawings
FIG. 1 is a schematic diagram of the working flow of on-line solid phase extraction analysis.
FIG. 2 is a chromatogram of kanamycin in a standard solution according to the present invention;
FIG. 3 is a chromatogram of kanamycin from spiked plasma samples 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.
Drawing of (II) standard curve
Firstly, 20uL of standard working solution is taken and placed in a 10mL centrifuge tube by a pipette gun, blank plasma is added to 1mL, the blank plasma is uniformly mixed to prepare standard solution with 6 concentrations, protein precipitator is respectively added into the standard solution for precipitation, after the standard solution is centrifuged for 10-15min by a centrifuge with the rotation speed of 15000rpm, 500uL of supernatant is respectively taken, a high performance liquid chromatograph and a DAD detector are used for detecting the supernatant to obtain a kanamycin spectrogram in the standard solution, kanamycin peak area is taken as the ordinate y of a standard curve graph, the concentration of kanamycin in the standard working solution is taken as the abscissa x of the standard curve graph, data is subjected to linear regression, a standard curve equation is obtained by fitting, the y is a x + b, and weight coefficients a, b and a related coefficient R2 are obtained. The standard curve is plotted at least three times with three different batches of standard working fluid. The standard working solution was a kanamycin-containing solution.
Preparing a standard working solution:
(a) accurately weighing 10mg of kanamycin standard substance, placing the kanamycin standard substance in a 1mL volumetric flask, dissolving the kanamycin standard substance with methanol and fixing the volume to obtain standard stock solution A, wherein the concentration of the kanamycin is 10mg/mL, diluting the standard stock solution A with blood plasma, preparing standard working solution with each concentration in the range of 15-600 mu g/mL of kanamycin respectively, and storing the standard working solution 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 kanamycin chromatogram of the sample to be detected, substituting a kanamycin peak area y in the chromatogram into a standard curve equation y ═ a x + b in the step (two), and calculating to obtain the concentration of kanamycin 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 kanamycin solutions with the concentrations of 0.5, 2.5, 5.5, 9.0, 13.0 and 18.0 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 0.04 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 mobile phase contains 30:70 ratio of organic phases: an aqueous phase, wherein the organic phase is acetonitrile, the aqueous phase is an aqueous solution containing 0.04% phosphoric acid, the flow rate of an analytical chromatographic column is 1.0mL/min, and the analytical chromatographic column adopts an isocratic elution mode;
the DAD detector is Thermo DAD-3000, and the detection wavelength is 218 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 the prepared 20. mu.L of kanamycin standard working solution with various concentrations, uniformly mixing, diluting, injecting a sample, determining the concentration of kanamycin from 0.3mg/L to 12mg/L according to the determination conditions of the embodiment from low to high, and drawing by using a quantitative chromatographic peak area-concentration to obtain a standard curve, wherein the result shows that the linear range and the quantitative limit of kanamycin are as follows:
(1) limit of detection (LOD): 0.1 mg/L.
(2) Limit of quantitation (LOQ): 0.6 mg/L.
(3) Linear range:
kanamycin is in the range of 0.6mg/L to 18mg/L, the linearity is good, and the correlation coefficient R2＞0.99。
Second, the recovery rate and precision of the method
Kanamycin standard working solution is prepared into high, medium and low concentrations for sample adding recovery rate experiments and precision experiments, the test is carried out according to the method of the embodiment, and the analysis and the measurement are repeated for 3 batches, wherein the recovery rate and the precision are respectively shown in the table 1. The average recovery rate of the kanamycin is 91.6-101.7% in the range of 3 addition levels of low, medium and high, the relative standard deviation is 1.29-1.73%, and the kanamycin standard addition recovery rate and the kanamycin precision are shown in a table 1.
| Addition amount/(mg/L) | 1.0 | 8.0 | 16.0 |
| Average recovery rate/%) | 91.6 | 101.7 | 96.1 |
| Precision RSD/%) | 1.29 | 1.73 | 1.49 |
TABLE 1 kanamycin spiking recovery and precision
Thirdly, stability of the solution
The prepared kanamycin precision sample is taken, and the stability of the sample solution is measured according to the method of the embodiment. The results of the experiment show that the sample is stable within 7 hours.
By integrating the verification tests, the technical indexes of the method, such as detection limit, recovery rate, precision, stability and the like, meet the requirements, the method for detecting the concentration of the kanamycin drug in blood has good reproducibility and high sample recovery rate, and the accuracy of the detection result is improved.
The kanamycin chromatogram in the standard solution is shown in figure 2, the kanamycin chromatogram in the serum sample is shown in figure 3, the kanamycin retention time is 14.93min, and as can be seen from figure 2 and figure 3, the target compound is accurately identified, the analysis time is short, the interference is small, and the specificity is strong.
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 on-line solid phase extraction liquid chromatography for detecting the kanamycin 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 taking 20uL standard working solution, adding blank plasma to 1ml, uniformly mixing to obtain standard solutions with 6 concentrations, respectively adding a protein precipitator into the obtained standard solutions for precipitation, centrifuging 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 kanamycin spectrogram in the standard solutions, taking the peak area of kanamycin as the ordinate y of a standard curve graph, taking the concentration of kanamycin in the standard working solution as the abscissa x of the standard curve graph, performing linear regression on 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(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 kanamycin;
(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, removing the sample to be detected 600 and 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 kanamycin chromatogram of the sample to be detected, substituting the kanamycin 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 kanamycin 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 kanamycin solution with the concentration of 0.5, 2.5, 5.5, 9.0, 13.0 and 18.0 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 0.03-0.05% 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 30% organic phase and a 70% aqueous phase, the organic phase is acetonitrile, and the aqueous phase is a 0.03-0.05% 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 218 nm.
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