CN103226142B - The detection method of leucogen concentration in a kind of blood plasma - Google Patents
The detection method of leucogen concentration in a kind of blood plasma Download PDFInfo
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- CN103226142B CN103226142B CN201110405011.4A CN201110405011A CN103226142B CN 103226142 B CN103226142 B CN 103226142B CN 201110405011 A CN201110405011 A CN 201110405011A CN 103226142 B CN103226142 B CN 103226142B
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- leucogen
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Abstract
The invention provides the detection method of leucogen concentration in a kind of blood plasma.Leucogen in blood plasma and tinidazole are used LC MS method to carry out separation determination after perchloric acid precipitation's albumen by the method.Through Method validation accurately and reliably, the concentration that can be used for leucogen in blood plasma measures the method for the present invention.
Description
Technical field
The present invention relates to the detection method of leucogen concentration in a kind of blood plasma, use liquid chromatograph-matter particularly to one
The method that spectrum multiple techniques analyzes leucogen concentration.
Background technology
Leucogen is drug for increasing white cells, for the leukopenia preventing and treating a variety of causes to cause, aplastic
Anemia and thrombocytopenia etc., chemistry is entitled: 2-(α-phenyl-α-carbethoxyl group-methyl) Thiazolidine-4-carboxylic acid.
The existing many of pharmacology activity research to leucogen, but in biological sample, the concentration of leucogen measures and medicine generation
Dynamics research report does not but have.
It addition, leucogen exists 3 chiral centres, there is mulitiple chiral centers, therefore it provides one can detect institute reliably
The method having these isomers just becomes the thing of actively difficulty.
Summary of the invention
The invention solves the problems that and technical problem is that, overcome the defect of prior art, it is provided that a kind of simple, quick, sensitive survey
Determine the method for leucogen blood drug level in blood plasma.
The invention provides the detection method of leucogen concentration in a kind of blood plasma, comprise the steps of
A () carries out pre-treatment to plasma sample: take testing sample, adds internal standard and perchloric acid carries out albumen precipitation, and take
Supernatant, described in be designated as tinidazole, its consumption for make in sample containing tinidazole concentration be 100ng-1mg/ml, described height
The consumption of solution chlorate is that in every 1ml sample, addition perchloric acid weight is 10-100mg.
The concentration of leucogen in (b) employing liquid chromatography-mass spectrography (LC-MS) combined instrument above-mentioned supernatant of mensuration, wherein,
Associated with LC-MS, chromatographic condition is: chromatographic column is to be filler with octadecylsilane chemically bonded silica；Internal standard method, with tinidazole
As internal standard；Flowing is the mixed liquor of acetonitrile-water-glacial acetic acid mutually, its volume ratio scope be 20 ± 1:80 ± 5:0.3 ±
0.03)；Associated with LC-MS, Mass Spectrometry Conditions is: ion source is ESI ion source, and cation detects.
In described step (a), perchloric acid can be pre-configured to aqueous solution, and concentration is 1-10%, preferably 3-7%, most preferably
4%。
In described step (a), tinidazole can be pre-configured to aqueous solution, and concentration is 1.0-1.5 μ g/ml.
Described analyzes the detection method of the side of leucogen content in blood plasma, and chromatographic condition flows by acetonitrile-water-ice second
Acid composition, its proportioning is acetonitrile-water-glacial acetic acid=20:80:0.3.
Described detection method, it is characterised in that in step LC-MS combination Mass Spectrometry Conditions, scan mode is selectivity
Ion detection.
Above-mentioned chromatographic condition is representative condition, different characteristics according to used instrument in actual application, can be to each ginseng
Number makes suitably adjustment, to obtaining optimal effect.The present invention establishes LC-MS method simple, sensitive, quick and measures blood plasma
The concentration of middle leucogen, its high sensitivity, less sample requirements and relatively short analysis time makes side of the present invention
Method is applicable to the clinical front and clinical medicine dynamics research from generation to generation of leucogen, utilizes the method, can well separation detection profit
Can monarch and diastereomer thereof.
Accompanying drawing explanation
Fig. 1 is the structural formula of leucogen.
Fig. 2 A is the mass spectrum full scan figure of leucogen.
Fig. 2 B is the mass spectrum full scan figure of tinidazole.
Fig. 3 A-3C is leucogen and the total ions chromatogram of tinidazole in embodiment one, and I represents the chromatograph of tinidazole
Peak, II, III, IV and V represents four kinds of diastereomers of leucogen respectively；Wherein: Fig. 3 A represents blank plasma；Fig. 3 B generation
Table blank plasma adds leucogen and internal standard tinidazole；Fig. 3 C represents plasma sample.
Fig. 4 A-4C is leucogen and the total ions chromatogram of tinidazole in another embodiment, and I represents the chromatograph of tinidazole
Peak, II, III, IV and V represents four kinds of diastereomers of leucogen respectively；Wherein: Fig. 4 A represents blank plasma；Fig. 4 B generation
Table blank plasma adds leucogen and internal standard tinidazole；Fig. 4 C represents plasma sample.
Detailed description of the invention
Embodiment one
1 instrument, material and reagent
1.1 instruments LC-MS combined instrument (Shimadzu LC-MS2020)
1.2 samples and reagent leucogen (purity is ＞ 99.5%)；Tinidazole (purity ＞ 99.8%), purchased from China's medicine
Biological products assay institute；Other chemical reagent are analytical pure.
2 experimental sections
The rat plasma sample 100 μ L that 2.1 plasma sample pre-treatments gather after taking intravenous administration is placed in 1.5mL and moulds
In material Ep pipe, add 30 μ L inner mark solution (1140ng/mL), vortex mixed 30s, add 100 μ L4% perchloric acid solutions, vortex
Mixing 3min, under the conditions of 4 DEG C, 20000rpm is centrifuged 10min twice, takes supernatant 10 μ L and carries out LC-MS analysis.
2.2 LC-MS analysis conditions
2.2.1 chromatographic condition chromatographic column: Agilent ZORBAX Eclipse Plus C18 (2.1*150mm, 5-
Micro)；Flowing phase: acetonitrile: water: glacial acetic acid=20;80;0.3；Column temperature: 30 DEG C；Flow velocity: 0-4min is 0.3mL/min, 4-
5min is linearly risen to 0.6mL/min by 0.3mL/min, maintains 0.6mL/min to terminate to analysis time；Sample size: 10 μ L.
2.2.2 Mass Spectrometry Conditions ESI ion source, cation detects；Scan mode: selectivity ion detection；Quantitative analysis
Ion be respectively as follows: m/z 296.2(leucogen) and m/z 248.1(tinidazole, internal standard).
2.3 LC-MS analysis results
The scanning of the mass spectrum figure of sample leucogen and internal standard tinidazole is seen Fig. 2 A and Fig. 2 B.
3 method confirmations
In 3.1 specificity this method, determinand is grasped with method with in standard curve concentration point with interior target specificity
The blank plasma made carries out contrast and is evaluated.
Blank plasma, blank plasma add the chromatogram of leucogen and internal standard tinidazole, plasma sample see respectively Fig. 3 A,
3B and 3C, it can be seen that the endogenous material in blank plasma does not disturb leucogen and interior target to measure, internal standard replaces nitre
The retention time of azoles is 3.2min, the retention time of four diastereomers of leucogen be respectively 9.5min, 10.6min,
11.9min and 13.2min.
3.2 is linear and the standard series working solution of sensitivity leucogen is by acetontrile.Take blank plasma 100 μ L, add
Enter inner mark solution 30 μ L, sequentially add leucogen standard series working solution designated volume, be configured to be equivalent to plasma concentration be
50,100,200,400,1000,2000,5000 and the plasma sample of 10000ng/mL, operate under 2.1, carry out LC-MS and divide
Analysis, tries to achieve linear regression equation, is working curve.It measures and analysis result is shown in Table 1.
The standard curve of table 1 leucogen
| Concentration (ng/mL) | 50 | 100 | 200 | 400 | 1000 | 2000 | 5000 | 10000 |
| Analog value (in A sample/A) | 0.2413 | 0.2696 | 0.7651 | 0.9645 | 1.6370 | 4.9575 | 16.8421 | 35.3485 |
The range of linearity of this method is 50 ~ 10000ng/mL, and the equation of standard curve is: y=0.003556x-
0.70697 (r2=0.994999), y represents the ratio of determinand and interior target peak area, and x represents the concentration of determinand.This method
Lowest detectable limit and minimum quantitative limit are respectively 10ng/mL (S/N=3) and 50ng/mL (S/N=10).
3.3 extraction recoveries take blank plasma 100 μ L, operate, prepare the sample of basic, normal, high three concentration under 3.2
Product are analyzed, and record chromatographic peak.Meanwhile, separately take pure water and replace blank plasma, operate under 3.2, prepare basic, normal, high by three
The sample of individual concentration is analyzed, it is thus achieved that respective peaks area, and with the ratio of the peak area of the two chromatogram, the extraction investigating sample is returned
Yield.Measure and analysis result is shown in Table 2.
The extraction recovery of table 2 leucogen
It is as shown in the table, the extraction recovery of three concentration leucogen is respectively 77.38 ± 6.14%, 81.45 ± 5.35%,
97.44±3.78%。
3.4 precision operate under 3.2 with accuracy, prepare the quality control of basic, normal, high three concentration of leucogen
Sample, each concentration carries out 6 sample analyses, METHOD FOR CONTINUOUS DETERMINATION three days, method precision by try to achieve in a few days, RSD(% in the daytime) comment
Valency, accuracy is obtained deviation by actually measured value and theoretical value and evaluates, and analysis result is as shown in table 3.
The veracity and precision of leucogen LC-MS assay method in table 3 plasma sample
As shown in table 3, in a few days, day to day precision respectively within 5.69% and 7.71%, accuracy range is 86.4 ~
112.5%, show that this method has good precision and accuracy.
3.5 stability investigate the stability of leucogen with-20 DEG C of freezings 10 days and freezing-dissolve three times, such as fruit
The deviation of measured value and theoretical value within ± 15%, then shows that sample is stable, and the stability result of this experimental technique is shown in Table 4.
Table 4 stability result
As shown in table 4, the measured value of leucogen concentration and the deviation of theoretical value, within ± 15%, show that this method has
Good stability.
Embodiment two
1 instrument, material and reagent
1.1 instrument LC-MS combined instruments
1.2 samples and reagent leucogen (purity is ＞ 99.5%)；Tinidazole (purity ＞ 99.8%), purchased from China's medicine
Biological products assay institute；Other chemical reagent are analytical pure.
2 experimental sections
The rat plasma sample 100 μ L that 2.1 plasma sample pre-treatments gather after taking gastric infusion is placed in 1.5mL plastics Ep
Guan Zhong, adds 30 μ L inner mark solution (1100ng/mL), vortex mixed 30s, adds 100 μ L6.2% perchloric acid solutions, and vortex mixes
Closing 5min, under the conditions of 4 DEG C, 20000rpm is centrifuged 150min twice, takes supernatant 10 μ L and carries out LC-MS analysis.
2.2 LC-MS analysis conditions
2.2.1 chromatographic condition chromatographic column: octadecylsilane chemically bonded silica is filler；Flowing phase: acetonitrile: water: ice
Acetic acid=21;85;0.33；Column temperature: 30 DEG C；Flow velocity: 0-4min is that 0.35mL/min, 4-5min are linearly risen to by 0.35mL/min
0.7mL/min, maintains 0.7mL/min to terminate to analysis time；Sample size: 10 μ L.
2.2.2 Mass Spectrometry Conditions ESI ion source, cation detects；Scan mode: selectivity ion detection；Quantitative analysis
Ion be respectively as follows: m/z 296.2(leucogen) and m/z 248.1(tinidazole, internal standard).
2.3 LC-MS analysis results
The scanning of the mass spectrum figure of sample leucogen and internal standard tinidazole is seen Fig. 2 A and Fig. 2 B.
3 method confirmations
In 3.1 specificity this method, determinand is grasped with method with in standard curve concentration point with interior target specificity
The blank plasma made carries out contrast and is evaluated.
Blank plasma, blank plasma add the chromatogram of leucogen and internal standard tinidazole, plasma sample see respectively Fig. 3 A,
3B and 3C, it can be seen that the endogenous material in blank plasma does not disturb leucogen and interior target to measure, internal standard replaces nitre
The retention time of azoles is 3.2min, the retention time of four diastereomers of leucogen be respectively 9.5min, 10.6min,
11.9min and 13.2min.
3.2 is linear and the standard series working solution of sensitivity leucogen is by acetontrile.Take blank plasma 100 μ L, add
Enter inner mark solution 30 μ L, sequentially add leucogen standard series working solution designated volume, be configured to be equivalent to plasma concentration be
50,100,200,400,1000,2000,5000 and the plasma sample of 10000ng/mL, operate under 2.1, carry out LC-MS and divide
Analysis, tries to achieve linear regression equation, is working curve.It measures and analysis result is shown in Table 5.
The standard curve of table 5 leucogen
| Concentration (ng/mL) | 50 | 100 | 200 | 400 | 1000 | 2000 | 5000 | 10000 |
| Analog value (in A sample/A) | 0.0399 | 0.0849 | 0.1895 | 0.3161 | 1.4369 | 2.8029 | 9.1374 | 20.3577 |
The range of linearity of this method is 50 ~ 10000ng/mL, and the equation of standard curve is: y=0.002039x-
0.48431 (r2=0.995685), y represents the ratio of determinand and interior target peak area, and x represents the concentration of determinand.This method
Minimum detectability and lowest detectable limit are respectively 10ng/mL (S/N=3) and 50ng/mL (S/N=10).
3.3 extraction recoveries take blank plasma 100 μ L, operate, prepare the sample of basic, normal, high three concentration under 3.2
Product are analyzed, and record chromatographic peak.Meanwhile, separately take pure water and replace blank plasma, operate under 3.2, prepare basic, normal, high by three
The sample of individual concentration is analyzed, it is thus achieved that respective peaks area, and with the ratio of the peak area of the two chromatogram, the extraction investigating sample is returned
Yield.Measure and analysis result is shown in Table 6.
The extraction recovery of table 6 leucogen
It is as shown in the table, the extraction recovery of three concentration leucogen is respectively 77.38 ± 6.14%, 81.45 ± 5.35%,
97.44±3.78%。
3.4 precision operate under 3.2 with accuracy, prepare the quality control of basic, normal, high three concentration of leucogen
Sample, each concentration carries out 6 sample analyses, METHOD FOR CONTINUOUS DETERMINATION three days, method precision by try to achieve in a few days, RSD(% in the daytime) comment
Valency, accuracy is obtained deviation by actually measured value and theoretical value and evaluates, and analysis result is as shown in table 7.
The veracity and precision of leucogen LC-MS assay method in table 7 plasma sample
As shown in table 3, in a few days, day to day precision respectively within 6.43% and 7.82%, accuracy range is 85.9 ~
114.1%, show that this method has good precision and accuracy.
3.5 stability investigate the stability of leucogen with-20 DEG C of freezings 10 days and freezing-dissolve three times, such as fruit
The deviation of measured value and theoretical value within ± 15%, then shows that sample is stable, and the stability result of this experimental technique is shown in Table 4.
Table 8 stability result
As shown in table 8, the measured value of leucogen concentration and the deviation of theoretical value, within ± 15%, show that this method has
Good stability.
Claims (7)
1. the detection method of leucogen concentration in a blood plasma, it is characterised in that comprise the steps of
A () carries out pre-treatment to plasma sample: take testing sample, adds internal standard and perchloric acid solution carries out albumen precipitation, and take
Supernatant, described in be designated as tinidazole, its consumption for make in sample containing tinidazole concentration be 100ng-1mg/ml, described height
The consumption of solution chlorate is that in every 1ml sample, addition perchloric acid weight is 10-100mg；
B () uses LC-MS combined instrument to measure the concentration of leucogen in above-mentioned supernatant, wherein, chromatographic condition associated with LC-MS
It is: chromatographic column is to be filler with octadecylsilane chemically bonded silica；Internal standard method, using tinidazole as internal standard；Flowing is second mutually
The mixed liquor of nitrile-water-glacial acetic acid, its proportion is 20 ± 1:80 ± 5:0.3 ± 0.03；Associated with LC-MS, Mass Spectrometry Conditions is:
Ion source is ESI ion source, and cation detects.
Detection method the most according to claim 1, it is characterised in that the perchloric acid solution in step (a) is for being pre-configured with
Aqueous solution, concentration is 1-10%.
Detection method the most according to claim 2, it is characterised in that the perchloric acid solution in step (a) is for being pre-configured with
Aqueous solution, concentration is 3-7%.
Detection method the most according to claim 2, it is characterised in that the perchloric acid solution in step (a) is for being pre-configured with
Aqueous solution, concentration is 4%.
Detection method the most according to claim 1, it is characterised in that in step (a), tinidazole can be pre-configured to water-soluble
Liquid, concentration is 1.0-1.5 μ g/ml.
Detection method the most according to claim 1, it is characterised in that described chromatographic condition flows by acetonitrile-water-ice
Acetic acid forms, and its volume ratio is acetonitrile-water-glacial acetic acid=20:80:0.3.
Detection method the most according to claim 1, it is characterised in that in LC-MS combination Mass Spectrometry Conditions, scan mode is choosing
Selecting property ion detection.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2029466C1 (en) * | 1992-01-22 | 1995-02-27 | Юрий Юрьевич Ивницкий | Agent for increase of body mass, thymus, spleen and red marrow bone in animals |
| CN1746670A (en) * | 2005-07-15 | 2006-03-15 | 张宏业 | Quality inspection of Ricosi preparation |
| CN1865251A (en) * | 2005-12-23 | 2006-11-22 | 张宏业 | Leucogen diastereoisomeride structural confirmation and determination method |
| CN1948963A (en) * | 2006-10-12 | 2007-04-18 | 张宏业 | Quality detecting method for likejun |
-
2012
- 2012-01-30 CN CN201110405011.4A patent/CN103226142B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2029466C1 (en) * | 1992-01-22 | 1995-02-27 | Юрий Юрьевич Ивницкий | Agent for increase of body mass, thymus, spleen and red marrow bone in animals |
| CN1746670A (en) * | 2005-07-15 | 2006-03-15 | 张宏业 | Quality inspection of Ricosi preparation |
| CN1865251A (en) * | 2005-12-23 | 2006-11-22 | 张宏业 | Leucogen diastereoisomeride structural confirmation and determination method |
| CN1948963A (en) * | 2006-10-12 | 2007-04-18 | 张宏业 | Quality detecting method for likejun |
Non-Patent Citations (2)
| Title |
|---|
| 利可君的高效液相色谱测定条件的优化;吴悦 等;《海峡药学》;20071231;第19卷(第12期);37-38页 * |
| 探讨LC_MS技术在快速发现和鉴定药物有关物质及代谢产物中的应用;王雷娜 等;《药学进展》;20071231;第31卷(第8期);358-363页 * |
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