CN110243963A - A kind of LC-MS/MS detection method of Captopril in Human Plasma - Google Patents
A kind of LC-MS/MS detection method of Captopril in Human Plasma Download PDFInfo
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Abstract
The present invention relates to a kind of LC-MS/MS detection methods of Captopril in Human Plasma, take and are previously added vitamin c solution in whole blood sample, vitamin c solution 1.5molL‑1Aqueous solution, centrifugation obtains plasma sample, 500 μ L blood plasma are taken to be mixed into 100 μ L p-bromophenacyl bromide solution, p-bromophenacyl bromide solution is 2mg/mL acetonitrile solution, it is to be measured to be placed in -80 DEG C of refrigerators preservations for blood plasma after reaction 10min, 50 μ L test plasma samples are taken, inner mark solution is mixed into, inner mark solution is the isotopic label captopril-d that acetonitrile is configured to3Concentration is the solution of 200ng/mL, is centrifuged after adding acetonitrile backwash oscillation 10min, supernatant is taken to carry out LC-MS/MS analysis.The present invention solves the problems, such as that captopril is unstable during biological sample analysis, improves the accuracy and reliability of analysis method, has the characteristics that few accuracy height, sample consumption, high sensitivity, detection flux are high compared with prior art.
Description
Technical field
The present invention relates to block in a kind of analyzing detecting method of captopril in biological sample more particularly to a kind of human plasma
The LC-MS/MS detection method of Top's benefit.
Background technique
Captopril is competitive angiotensin converting enzyme inhibitor, and indication is hypertension and heart failure.Kato
Containing a unstable sulfydryl (- SH) in Puli's structure, it is easy to and protein cysteine sulfydryl, the glutathione etc. in blood plasma
Covalent bond occurs for substance containing free sulfhydryl groups, generates disulphide；This reaction in vivo and can all occur in vitro；Captopril
The amount of about half is biologically converted into disulphide in vivo；It is placed outside the matrix bodies such as captopril whole blood or blood plasma
In the process, curing reaction can occur rapidly, captopril concentration is caused quickly to reduce, be easy to cause and measured in human plasma
Captopril concentration is relatively low, and then influences the evaluation results such as Drug safety, validity, consistency；It uses in the prior art
The derivatizations such as p-bromophenacyl bromide actually perform the derivatization blood plasma, but the technology does not solve captopril shakiness in whole blood
Fixed problem；Strong reductant such as dithiothreitol (DTT) is used in other technology, and Captopril in Human Plasma disulphide is converted
For captopril, this can make measurement concentration higher；There is also blood plasma dosages for the prior art greatly, detection flux is low, sensitivity is low etc.
Problem.
It would therefore be highly desirable to develop a kind of sample-pretreating method, solve the problems, such as that captopril is unstable in bio-matrix,
In conjunction with LC-MS/MS detection technique, accurately Captopril in Human Plasma concentration is determined, while realizing high throughput.
Summary of the invention
It is high that it is an object of that present invention to provide a kind of accuracy, is suitble to the Captopril in Human Plasma of batch samples detection
LC-MS/MS detection method.
To achieve the goals above, the present invention provides a kind of LC-MS/MS detection method of Captopril in Human Plasma,
The following steps are included:
A kind of LC-MS/MS detection method of Captopril in Human Plasma, which comprises the following steps:
S1: sample pre-treatments, for acquisition blood sample about 3mL in the anticoagulant tube containing 50 μ L vitamin c solutions, centrifugation obtains blood plasma
Sample takes 500 μ L plasma samples, is mixed into 100 μ L p-bromophenacyl bromide solution, and blood plasma is placed in -80 DEG C of ice after reacting 10min
Case saves to be measured；50 μ L test plasma samples are taken, inner mark solution is mixed into, inner mark solution is the isotopic label that acetonitrile is configured to
Captopril-d3 concentration is the solution of 200ng/mL, is centrifuged after adding acetonitrile backwash oscillation 10min, supernatant is taken to carry out
LC-MS/MS analysis；The inner mark solution is that the isotopic label captopril-d3 concentration that acetonitrile is configured to is 200ng/mL
Solution；
S2: using the concentration of captopril in LC-MS/MS method measurement sample to be tested；
I. chromatographic condition: chromatographic column: 100 × 4.6mm, 3.5 μm；Column temperature: 40 DEG C；Sampling volume: 2 μ L；Mobile phase A: contain
There is the 2mM ammonium acetate aqueous solution of 0.2% formic acid；Mobile phase B: acetonitrile uses volume ratio for the A:B phase Gradient elution of 35:65,
Autosampler temperature is 4 DEG C, and the flow velocity of mobile phase is 1.1mL/min, shunts 0.4mL/min after center pillar and enters mass spectrum；
II. Mass Spectrometry Conditions: ion source: electrospray ionisation source ESI；Spray voltage 5500V；Ion source temperature: 600 DEG C；
CUR:40psi；Scan pattern: cation multiple-reaction monitoring+MRM, captopril and captopril-d3 ionic reaction are respectively m/
Z 414.4 → 216.2 and m/z 417.1 → 219.2, collision energy CE are respectively 23 and 25eV；
S3: the preparation of standard curve sample weighs card holder Puli with methanol dissolution and constant volume, and being configured to concentration is about
The stock solution of 1.00mg/mL, with acetonitrile: water dilutes step by step obtains standard series working solution, dilutes the work with people's blank plasma
Make solution, standard curve sample is made, vitamin C is added into standard curve sample immediately after the completion and to Bromophenac rLl
Bromine solutions after reacting 10min, are detected, and draw according to testing result with the processing method of above-mentioned steps S1 and LC-MS/MS condition
Make the standard curve of corresponding captopril.
Preferably, vitamin c solution described in the step S1 is 1.5mol.L-1 aqueous solution.
Preferably, p-bromophenacyl bromide solution described in the step S1 is 2.00mg/mL acetonitrile solution.
According to the above aspect of the present invention, the present invention has at least the following advantages:
1, dimension is added in the whole blood sample in the LC-MS/MS detection method of Captopril in Human Plasma provided by the invention
Raw element C, it can be ensured that stability of the captopril in whole blood, after whole blood is centrifuged blood plasma, using to Bromophenac rLl
Bromine is by captopril derivatization, it is ensured that the stability of captopril during subsequent analysis.
2, the present invention solves the problems, such as that captopril is unstable during biological sample analysis, improves analysis method
Accuracy and reliability, have that accuracy is high, sample consumption is few, high sensitivity, detection flux are high compared with prior art
The characteristics of.
3, the present invention provides stable, accurate, practical side for the measurement of Captopril tablets pharmacokinetic studies plasma sample
Method.
The above description is only an overview of the technical scheme of the present invention, in order to better understand the technical means of the present invention,
And can be implemented in accordance with the contents of the specification, the following is a detailed description of the preferred embodiments of the present invention and the accompanying drawings.
Detailed description of the invention
Fig. 1 be captopril in the LC-MS/MS detection method of Captopril in Human Plasma provided by the invention product from
Son scanning mass spectrogram；
Captopril-d in the LC-MS/MS detection method of Fig. 2 Captopril in Human Plasma provided by the invention3Product
Ion scan mass spectrogram；
Fig. 3 be captopril in blank plasma samples in embodiment one (on) and captopril-d3(under) MRM chromatogram；
Fig. 4 be captopril in LLOQ plasma sample in embodiment one (on) and captopril-d3(under) MRM chromatogram；
Fig. 5 is 1 subject's period 1 and second round pharmaceutical concentration-time curve in embodiment two.
Specific embodiment
With reference to the accompanying drawings and examples, specific embodiments of the present invention will be described in further detail.Implement below
Example is not intended to limit the scope of the invention for illustrating the present invention.
In order to enable those skilled in the art to better understand the solution of the present invention, below in conjunction with attached in the embodiment of the present invention
Figure, technical scheme in the embodiment of the invention is clearly and completely described, it is clear that described embodiment is only this
Invention a part of the embodiment, instead of all the embodiments.Embodiments of the present invention, which are generally described and illustrated herein in the accompanying drawings
Component can arrange and design with a variety of different configurations.Therefore, the implementation of the invention to providing in the accompanying drawings below
The detailed description of example is not intended to limit the range of claimed invention, but is merely representative of selected implementation of the invention
Example.Based on the embodiment of the present invention, those skilled in the art are obtained all without making creative work
Other embodiments shall fall within the protection scope of the present invention.
Embodiment one
Abbreviation explanation
As shown in Figures 1 to 4, the foundation of Captopril in Human Plasma LC-MS/MS measuring method
1, the preparation of solution and sample
1.1 standard series samples: precision weighs that captopril is appropriate according to product, and with methanol dissolution and constant volume, precision is drawn each
Appropriate from stock solution, with acetonitrile: water (1:1, v/v) dilutes step by step obtains standard series working solution, with the dilution of people's blank plasma
The working solution, it is 2.00~800ng/mL that standard curve sample captopril concentration range, which is made, after the completion immediately to standard
Vitamin C and p-bromophenacyl bromide solution are added in curve sample, after reacting 10min, for drawing standard curve；
1.2 quality-control samples: four concentration level Quality Control samples of captopril are prepared using with standard series sample similar method
Product, lower limit of quantitation (lower limit of quantification, LLOQ) concentration are 2.00ng/mL, low-quality control (low
Quality control, LQC) concentration is 6.00ng/mL, middle Quality Control (medium quality control, MQC) concentration is
50.0ng/mL, high Quality Control (high quality control, HQC) concentration are 640ng/mL；
1.3 inner mark solutions: 1mg captopril-d is quantitatively shifted3Reference substance is configured to Kato with methanol dissolution and constant volume
Puli-d3Concentration is the internal standard stock solution of 93.4 μ g/mL, and precision absorption internal standard stock solution is appropriate, adds acetonitrile: water (1:1, v/v)
Dilution obtains captopril-d3Concentration is respectively the solution of 250ng/mL, takes the above-mentioned solution of 98.0mL, the dense of 24.5mL is added
Degree is the p-bromophenacyl bromide acetonitrile solution of 2.00mg/mL, is vortexed 30s, after standing 10min, then is vortexed 30s, is obtained dense
Degree is 200ng/mL inner mark solution.
2, sample pre-treatments
Blood sample about 4mL is acquired in the anticoagulant tube containing 50 μ L vitamin C aqueous solutions, centrifugation obtains plasma sample, takes 500 μ L
Blood plasma is mixed into 100 μ L p-bromophenacyl bromide acetonitrile solutions, and it is to be measured to be placed in -80 DEG C of refrigerators preservations for blood plasma after reaction 10min；It takes
50 μ L test plasma samples, are mixed into inner mark solution, are centrifuged after adding acetonitrile backwash oscillation 10min, supernatant is taken to carry out LC-
MS/MS analysis.
3, detecting instrument and analysis condition
3.1 Japan's Shimadzu Corporation LC-30AD fast liquid chromatography systems, and adding equipped with electrospray ionisation source (ESI)
Put on airs Sciex company's T riple QuadTM 6500+Type triple quadrupole bar tandem mass spectrometer.
3.2 analysis condition
3.2.1 chromatographic condition: chromatographic column using Agilent company of the U.S. Eclipse Plus-C18 (100 × 4.6mm, 3.5
μm), 40 DEG C of column temperature, autosampler is set as 4 DEG C, and mobile phase A is the 2mM ammonium acetate aqueous solution containing 0.2% formic acid, mobile phase
B is acetonitrile, is eluted using 65%B equality, and flow velocity 1.1mL/min (shunts 0.4mL/min) after column, 2.00 μ L of sample volume；
3.2.2 Mass Spectrometry Conditions: electrospray ionisation source ESI；Spray voltage 5500V；Ion source temperature: 600 DEG C；CUR:
40psi；Scan pattern: cation multiple-reaction monitoring+MRM monitors captopril and captopril-d3Ionic reaction is respectively m/
Z 414.4 → 216.2 and m/z 417.1 → 219.2, collision energy CE are respectively 23 and 25eV.
4, methodology validation
Methodology validation carried out to this method according to Chinese Pharmacopoeia and U.S. FDA guideline, content include stability,
Selectivity, linear, accuracy, precision, residual effect, the rate of recovery, matrix effect and dilution reliability.
4.1 selectivity
It takes after six different blank plasmas in source and the LLOQ sample treatment respectively prepared that sample introduction is analyzed, obtains blank blood
Captopril MRM chromatogram Fig. 3 and LLOQ sample captopril MRM chromatogram Fig. 4, chromatography flow out chaff interferent altogether in slurry samples
Peak area is respectively less than the 20% of LLOQ determinand peak area, less than the 5% of internal standard peak area.
4.2 preci-sion and accuracy
Method validation analyzes each six samples of Quality Control sample of four concentration of every a batch measurement, METHOD FOR CONTINUOUS DETERMINATION three batches, calculates
With betweenrun precision and accuracy in batch, LLOQ batches of interior, betweenrun precisions can less than 20% side with relative standard deviation (RSD) calculating
Receive, accuracy with relative deviation calculate (RE) can receive between ± 20%, the QC sample of remaining each concentration level respectively at
In batches interior, betweenrun precision need to can receive less than 15% side, and accuracy can receive between ± 15%, the results are shown in Table 1.
Table 1:
Measure the preci-sion and accuracy of Captopril in Human Plasma
4.3 standard curve
Using determinand theoretical concentration as abscissa (x), the peak area ratio of determinand and internal standard compound is ordinate (y), with adding
Weigh (W=1/x2) least square method progress regressing calculation, the linear regression equation acquired is standard curve, and method validation is each
Analysis batch obtains captopril plasma sample standard curve linear equation y=to standard curve sample two-sample analysis
0.00103x+0.000418 (r=0.9989) indicates captopril linear relationship in the concentration range of 2.00~800ng/mL
Well.
4.4 residual effect
Residual effect is verified as after high concentration pattern detection analyzing captopril and internal standard appearance with blank sample sample introduction
The response of instrument at time.The sample introduction blank plasma samples after upper limit of quantification sample, blank sample captopril retention time
The chromatographic peak area at place is respectively less than the 20% of same day standard curve lower limit of quantitation peak area, chromatographic peak area at internal standard retention time
Respectively less than the same day marks the 5% of bent lower limit of quantitation internal standard peak area.
4.5 extraction recovery
Basic, normal, high three concentration Quality Control plasma sample is prepared, each concentration carries out 6 sample analyses, separately takes blank plasma,
In addition to internal standard is not added, same treatment is carried out, a certain concentration contrast solution is added into the supernatant of acquisition, makes determinand and internal standard most
Treated that theoretical concentration is identical with basic, normal, high quality-control sample respectively for final concentration, and each concentration carries out 6 sample analyses, with each
The rate of recovery of the calculated by peak area rate of recovery of two kinds of processing methods of concentration, basic, normal, high three concentration of captopril is respectively
75.8%, 81.8% and 81.5%.Interior target extraction recovery is 95.8%.
4.6 matrix effect
Investigate the matrix effect under low, high two QC concentration levels.6 separate sources blank plasmas are taken, except internal standard is not added
Outside, it is operated by plasma sample preprocess method, into the supernatant of acquisition plus a certain concentration contrast solution, so that determinand and interior
It is identical as the theoretical concentration after low, high QC sample treatment respectively to mark ultimate density, carries out 3 sample analyses, while replacing sky with water
White blood plasma calculates separately internal normalization matrix factors under two kinds of processing modes, passes through with 3 sample analyses are carried out after method operation
The precision of matrix factors assesses matrix effect, and the RSD of separate sources blood plasma internal normalization matrix factors can less than 15% side
Receive.
Captopril is respectively 98.5% and 99.6% in low, high concentration internal normalization matrix effect factor mean value,
The RSD of separate sources blood plasma internal normalization matrix factors is respectively less than 2.2%, the above result shows that, matrix do not interfere prepare for TOFEL it is general
The measurement of benefit.
4.7 stability
Stability assessment covers the detection process of entire sample, and low concentration 6.00ng/mL and high concentration 640ng/mL is arranged
Two concentration, each concentration repeat 3 samples, investigate 1 hour stability of whole blood ice-water bath placement, plasma sample ice-water bath is put
4 DEG C of shelf-stabilities of sample after 8 hours stability, 48 days stability of -80 DEG C of placements, 4 multigelation stability, extractions are set,
Relative deviation (%) can receive between ± 15%, the results are shown in Table 2.
Table 2:
Captopril plasma stability
4.8. reliability is diluted
It prepares the plasma sample that captopril concentration is 3200ng/mL and takes 50.0 μ L blood after diluting five times with blank plasma
Slurry is pre-processed, and sample introduction is analyzed after being disposed, and each concentration prepares 6 samples, measures captopril dilution quality-control sample
Preci-sion and accuracy be respectively 2.7% and 6.9%.
Embodiment two
Measure the captopril in human plasma
Using the concentration of the Captopril in Human Plasma LC-MS/MS measuring method measurement Captopril in Human Plasma of foundation, use
In evaluation Captopril tablets bioequivalence Journal of Sex Research.
10 subjects are assigned randomly to TR sequence group and RT (test reagent T by 1:1；Reference preparation R) sequence group, by
Examination person empty stomach oral administration Captopril tablets 12.5mg (piece), the different time in 12 hours after medication 0h (before taking medicine in 1h) and medication
Point each acquisition blood sample about 4mL is centrifuged immediately in containing in ascorbic anticoagulant tube, derivatization reagent is added after isolating blood plasma, instead
Answer after 10min blood plasma be placed in -80 DEG C of refrigerators save it is to be measured.Pass through the Captopril in Human Plasma LC-MS/MS measuring method of foundation
Measure the concentration of captopril in subject's plasma sample.Wherein, Fig. 5 is 1 subject's period 1 and second round drug
Concentration time curve.
The present invention has at least the following advantages:
1, dimension is added in the whole blood sample in the LC-MS/MS detection method of Captopril in Human Plasma provided by the invention
Raw element C, it can be ensured that stability of the captopril in whole blood, after whole blood is centrifuged blood plasma, using to Bromophenac rLl
Bromine is by captopril derivatization, it is ensured that the stability of captopril during subsequent analysis.
2, the present invention solves the problems, such as that captopril is unstable during biological sample analysis, improves analysis method
Accuracy and reliability, have that accuracy is high, sample consumption is few, high sensitivity, detection flux are high compared with prior art
The characteristics of.
3, the present invention provides stable, accurate, practical side for the measurement of Captopril tablets pharmacokinetic studies plasma sample
Method.
The above is only a preferred embodiment of the present invention, it is not intended to restrict the invention, it is noted that for this skill
For the those of ordinary skill in art field, without departing from the technical principles of the invention, can also make it is several improvement and
Modification, these improvements and modifications also should be regarded as protection scope of the present invention.
Claims (3)
1. a kind of LC-MS/MS detection method of Captopril in Human Plasma, which comprises the following steps:
S1: sample pre-treatments, for acquisition blood sample about 3mL in the anticoagulant tube containing 50 μ L vitamin c solutions, centrifugation obtains blood plasma sample
Product take 500 μ L plasma samples, are mixed into 100 μ L p-bromophenacyl bromide solution, and blood plasma is placed in -80 DEG C of refrigerators after reacting 10min
It saves to be measured；50 μ L test plasma samples are taken, inner mark solution is mixed into, inner mark solution is the isotopic label card that acetonitrile is configured to
Top's benefit-d3 concentration is the solution of 200ng/mL, is centrifuged after adding acetonitrile backwash oscillation 10min, supernatant is taken to carry out LC-
MS/MS analysis；The inner mark solution is that the isotopic label captopril-d3 concentration that acetonitrile is configured to is the molten of 200ng/mL
Liquid；
S2: using the concentration of captopril in LC-MS/MS method measurement sample to be tested；
I. chromatographic condition: chromatographic column: 100 × 4.6mm, 3.5 μm；Column temperature: 40 DEG C；Sampling volume: 2 μ L；Mobile phase A: contain
The 2mM ammonium acetate aqueous solution of 0.2% formic acid；Mobile phase B: acetonitrile uses volume ratio for the A:B phase Gradient elution of 35:65, from
Dynamic sample injector temperature is 4 DEG C, and the flow velocity of mobile phase is 1.1mL/min, shunts 0.4mL/min after center pillar and enters mass spectrum；
II. Mass Spectrometry Conditions: ion source: electrospray ionisation source ESI；Spray voltage 5500V；Ion source temperature: 600 DEG C；CUR:
40psi；Scan pattern: cation multiple-reaction monitoring+MRM, captopril and captopril-d3 ionic reaction are respectively m/z
414.4 → 216.2 and m/z 417.1 → 219.2, collision energy CE are respectively 23 and 25eV；
S3: the preparation of standard curve sample weighs card holder Puli with methanol dissolution and constant volume, and being configured to concentration is about
The stock solution of 1.00mg/mL, with acetonitrile: water dilutes step by step obtains standard series working solution, dilutes the work with people's blank plasma
Make solution, standard curve sample is made, vitamin C is added into standard curve sample immediately after the completion and to Bromophenac rLl
Bromine solutions after reacting 10min, are detected, and draw according to testing result with the processing method of above-mentioned steps S1 and LC-MS/MS condition
Make the standard curve of corresponding captopril.
2. a kind of LC-MS/MS detection method of Captopril in Human Plasma according to claim 1, it is characterised in that: institute
Stating vitamin c solution described in step S1 is 1.5mol.L-1 aqueous solution.
3. a kind of LC-MS/MS detection method of Captopril in Human Plasma according to claim 1, it is characterised in that: institute
Stating p-bromophenacyl bromide solution described in step S1 is 2.00mg/mL acetonitrile solution.
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| CN112345660A (en) * | 2020-09-29 | 2021-02-09 | 杭州凯莱谱精准医疗检测技术有限公司 | Kit and method for determining activity of human plasma sample renin |
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| CN112345660A (en) * | 2020-09-29 | 2021-02-09 | 杭州凯莱谱精准医疗检测技术有限公司 | Kit and method for determining activity of human plasma sample renin |
| CN117129605A (en) * | 2023-10-25 | 2023-11-28 | 济南和合医学检验有限公司 | Method for detecting 11 antihypertensive drugs and 3 metabolites by liquid chromatography-tandem mass spectrometry |
| CN117129605B (en) * | 2023-10-25 | 2024-02-02 | 济南和合医学检验有限公司 | Method for detecting 11 antihypertensive drugs and 3 metabolites by liquid chromatography-tandem mass spectrometry |
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