CN106596824A - Method for detecting thalidomide in plasma by LC-MS/MS method - Google Patents
Method for detecting thalidomide in plasma by LC-MS/MS method Download PDFInfo
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- CN106596824A CN106596824A CN201611255733.5A CN201611255733A CN106596824A CN 106596824 A CN106596824 A CN 106596824A CN 201611255733 A CN201611255733 A CN 201611255733A CN 106596824 A CN106596824 A CN 106596824A
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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 discloses a method for detecting thalidomide in plasma by an LC-MS/MS method, comprising the steps: firstly, precisely measuring blank plasma, adding a series of thalidomide standard operating fluid, adding sodium citrate buffer fluid and internal standard umbelliferone standard operating fluid, carrying out pretreatment by adopting a liquid-liquid extraction method, analyzing by the LC-MS/MS method to obtain the chromatogram of each sample, and establishing a standard curve by taking the peak area ratio of the substance to be detected to the internal standard as a horizontal ordinate and the concentration of the substance to be detected as a longitudinal coordinate; then precisely measuring plasma to be detected, adding an equal volume of sodium citrate buffer fluid, then adding the internal standard umbelliferone standard operating fluid, carrying out pretreatment by the liquid-liquid extraction method, carrying out LC-MS/MS analysis to obtain the chromatogram of each sample, and calculating the concentration of the sample plasma by using the standard curve. The method is simple and quick in operation and high in sensitivity, accuracy and precision, uses safe non-poisonous solvents, and can meet the requirements on monitoring the concentration of a thalidomide medicament in clinical application.
Description
Technical field
The invention belongs to pharmacokinetic analysis technical field.Skill is combined more particularly, to a kind of using liquid chromatography mass spectrometric
The method of Thalidomide, can be used for the medicine therapeutic drug monitori in the detection blood plasma that art is carried out.
Background technology
Thalidomide（Thalidomide, THD）, trade name reaction stop, the twentieth century fifties is by German pharmaceutical business
Company of Glan Thailand releases and is widely used as tranquilizer and the medicine of prevention gestational vomiting is used, after cause new life because of Thalidomide
The congenital extremity of youngster are incomplete to be " reaction stops event " and is withdrawn by market.Find that Thalidomide has afterwards and suppress angiogenesis, suppression
Tumor necrosis factor processed and immunosuppressant etc. are acted on.It is clinically used at present treating ENL, multiple myeloma, class
Rheumatic arthritis, rheumatism and Complicated etc..
And Thalidomide may cause the untoward reaction such as peripheral neuritiss, dizziness, headache and constipation in Clinical practice.
The dose relationship of its clinical efficacy, untoward reaction and Thalidomide is not obvious, the accurate medication of appreciable impact Thalidomide, therefore
It is necessary the haemoconcentration for detecting medicine, the clinical rational drug use for Thalidomide provides crucial foundation.
At present, the detection method of Thalidomide mainly has high performance liquid chromatography and reversed phase high-performance liquid chromatography, the former
Sensitivity is low, and detection time is long, and the detection method of the current document report of the latter can not still fully meet clinical assays demand.
The content of the invention
The technical problem to be solved in the present invention is the defect and technical deficiency for overcoming above-mentioned prior art, sets up a kind of fast
Speed, the liquid chromatography mass combination that sensitivity is high, accuracy and precision are high（LC-MS/MS）Thalidomide is dense in detection blood plasma
The method of degree, meets the needs and purpose of clinical practice Thalidomide monitor drug concentration.
It is an object of the invention to provide a kind of method that LC-MS/MS methods detect Thalidomide in blood plasma.
Above-mentioned purpose of the present invention is achieved through the following technical solutions：
The method of Thalidomide, comprises the steps in a kind of LC-MS/MS methods detection blood plasma：Precision measures blank plasma, adds
A series of Thalidomide standard substance standard working solutions, add sodium citrate buffer solution and internal standard umbelliferone standard substance standard work
Make liquid, using liquid-liquid extraction method pre-treatment after, be analyzed using LC-MS/MS, each sample chromatogram is obtained, with determinand
It is abscissa with internal standard peak area ratio, by vertical coordinate of testing concentration standard curve is set up；It is then accurate to measure test plasma,
Equal-volume sodium citrate buffer solution is added, internal standard umbelliferone standard working solution is added, is located using before liquid-liquid extraction method
After reason, LC-MS/MS analyses are carried out, obtain the chromatogram of each sample, using standard curve the concentration of sample blood plasma is calculated.
Particularly preferably, the method that the LC-MS/MS methods detect Thalidomide in blood plasma, comprises the steps：
S1. standard working solution is prepared
Precision weighs Thalidomide and internal standard umbelliferone powder, dissolves and be diluted to standard working solution with lysate respectively；
The lysate is the mixed solution of methanol, acetonitrile and formic acid；
S2. standard curve is set up
Precision measures blank plasma, adds a series of Thalidomide standard working solutions, adds sodium citrate buffer solution and internal standard umbrella
Shape flower lactone standard working solution, using liquid-liquid extraction method pre-treatment, is analyzed afterwards using LC-MS/MS, obtains various kinds true qualities
Spectrogram, with determinand and internal standard peak area ratio as abscissa, by vertical coordinate of testing concentration standard curve is set up；
S3. testing sample detection
S31. sample to be tested blood plasma pre-treatment：Precision amount test plasma, adds equal-volume sodium citrate buffer solution, adds internal standard
Umbelliferone standard working solution（In right amount, 1/10th of plasma sample volume）, using liquid-liquid extraction method pre-treatment；
S32. it is analyzed using LC-MS/MS, obtains the chromatogram of each sample, using standard curve sample blood plasma is calculated
Concentration.
Wherein it is preferred to, the volume ratio of methanol, acetonitrile and formic acid is 45～55 in lysate described in step S1：44～54：
1。
It is highly preferred that the volume ratio of methanol, acetonitrile and formic acid is 50 in lysate described in step S1：49：1.
It is highly preferred that the compound method of the standard working solution of Thalidomide is specially in step S1：Precision weighs Sha Lidu
Amine standard substance, with DMSO standard reserving solution of the constant volume for 1000 μ g/ml is dissolved, then is 50 with volume ratio：49：1 methanol：Second
Nitrile：Formic acid mixed solution gradient dilution, is configured to a series of standard working solution of concentration.
A series of concentration of the standard working solution of concentration be 20,50,250,1000,2500,5000,10000,
20000 ng /ml。
It is highly preferred that the compound method of the standard working solution of internal standard umbelliferone is specially in step S1：Precision is weighed
Umbelliferone standard substance, are dissolved with methanol, are 50 with volume ratio：49：1 methanol：Acetonitrile：Formic acid mixed solution constant volume is
The standard reserving solution of 100 μ g/ml, facing the used time is diluted to standard working solution（Such as the standard working solution of 1000ng/ml）.
Preferably, step S2 or the agents useful for same of liquid-liquid extraction method pre-treatment described in S31 are ethyl acetate.
Preferably, the concrete grammar of the liquid-liquid extraction method pre-treatment is：Sample adds sodium citrate buffer solution and interior
After mark umbelliferone standard working solution, after vortex is mixed, the ethyl acetate of 2～2.5 times of volumes, vortex vibration is added to stand 3
After～8min, centrifuging and taking supernatant is volatilized in vacuum desiccator, and residue mobile phase is redissolved, after vortex mixing, in centrifuging and taking
Clearly, as need testing solution, for the analysis of LC-MS/MS sample introductions.
Wherein, the time that the vortex is mixed is 8～15s（It is preferred that 10s）.
The time of the vortex vibration is 0.8～1.5（Preferably 1 min）.
Preferably, the time of the standing is 5 min.
Preferably, the centrifugation is centrifuged 5～10 min for 15000 r/min.
Preferably, in above-mentioned LC-MS/MS analysis methods, using APCI source ions；The quantitative daughter ion of Thalidomide
For 186.1 m/z, qualitative daughter ion is 84.1 m/z, and interior scalar quantity daughter ion is 107.1 m/z.
Preferably, the volume of sodium citrate buffer solution described in step S2 is the total of blood plasma and Thalidomide standard working solution
With the volume of the internal standard umbelliferone standard working solution is identical with the volume of Thalidomide standard working solution.
Preferably, the concentration of step S2 or sodium citrate buffer solution described in S3 be 25mmol/L, with hydrochloric acid adjust PH to
1.5。
Preferably, the chromatographic condition mobile phase of step S2 or LC-MS/MS described in S3 is set as：Methanol：0.1% formic acid water
Volume ratio=70：30.
Preferably, the step S2 or chromatographic condition of LC-MS/MS is described in S3：The mLmin of flow velocity 0.5-1；The μ of sample size 20
L；25 DEG C of column temperature；MRM patterns：Thalidomide：m/z 259.03→m/z 84.13；m/z 259.03→m/z 186.05；7-
Hydroxycoumarin（Umbelliferone）：m/z 163.01→m/z 107.17.
Preferably, the chromatographic column of step S2 or LC-MS/MS described in S3 be BETASIL C18 chromatographic columns (4.6 mm ×
150 mm, 5µm; Thermo, USA)。
Preferably, present invention aqueous solution used is ultra-pure water, and organic reagent used is HPLC levels.
The invention has the advantages that：
The present invention establishes a kind of liquid chromatography mass that quick, sensitivity is high, accuracy and precision are high combination（LC-MS/
MS）The method of Thalidomide concentration in detection blood plasma, the present invention reflects due to having carried out reasonably optimizing to Sample pretreatment method
In Thalidomide unstable chemcial property, facile hydrolysiss, the present invention adds acidifying stabilizer, there is provided the plasma sample of efficient stable
Pre-treating method so that the method applied in the present invention is easy to operate, process time is short, using extractant safety non-toxic.
Meanwhile, the present invention has carried out reasonable setting to chromatographic condition so that using the determinand obtained by the method for the present invention
Reliable and stable with internal standard chromatogram, the detection technique sensitivity that the present invention is provided is high, and analysis time is short and accuracy and precision
Height, can preferably reach the purpose of Thalidomide clinical treatment drug monitoring.
Description of the drawings
Fig. 1 is the Thalidomide ion massspectrum figure of the foundation that the embodiment of the present invention 1 is set up.
Fig. 2 is the standard curve for determining Thalidomide concentration in human plasma that the embodiment of the present invention 1 is set up.
Fig. 3 is the sample chromatogram of the LC-MS/MS methods that the embodiment of the present invention 1 is set up.
Fig. 4 is the sample chromatogram of the LC-MS/MS methods that the embodiment of the present invention 2 is set up.
Fig. 5 is that the foundation measure patients with inflammatory bowel disease of the embodiment of the present invention 3 takes Thalidomide piece vivo medicine concentration knot
Really.
Specific embodiment
The present invention, but embodiment are further illustrated below in conjunction with Figure of description and specific embodiment not to the present invention
Limit in any form.Unless stated otherwise, reagent, the method and apparatus that the present invention is adopted is for the art routinely examination
Agent, method and apparatus.
Unless stated otherwise, agents useful for same of the present invention and material are commercial.
LC-MS/MS described in text is the abbreviation of liquid chromatography mass multiple techniques.
Embodiment 1 sets up the standard curve for determining Thalidomide concentration in blood plasma
1st, standard working solution is prepared：
（1）Precision weighs Thalidomide standard substance 0.0100g, is dissolved with 1ml DMSO, in moving into 10 ml volumetric flasks, uses DMSO
Constant volume shakes up the standard reserving solution for obtaining final product 1 000 μ g/ml to scale, is placed in -20 DEG C of preservations of refrigerator.Again with methanol：Second
Nitrile：Formic acid（50：49：1, v/v/v）Solution gradient dilute, compound concentration be 20,50,250,1000,2500,5000,10000,
The standard working solution of 20000 ng/ml, is placed in 4 DEG C of preservations of refrigerator.
（2）Precision weighs the g of umbelliferone standard substance 0. 005 0, is dissolved with methanol, in moving into 50 ml volumetric flasks,
Use methanol：Acetonitrile：Formic acid（50：49：1, v/v/v）Constant volume shakes up the standard reserving solution for obtaining final product 100 μ g/ml to scale, puts
In -20 DEG C of preservations of refrigerator.Face the standard working solution that the used time is diluted to 1000 ng/ml, be placed in 4 DEG C of preservations of refrigerator.
2nd, standard curve is set up
（1）Precision draws the μ l of blank plasma 90, and in being placed in the centrifuge tube of 5 ml, the THD standards for being separately added into variable concentrations are molten
The μ l of liquid 10, mix so as to which concentration is respectively 2,5,25,100,250,500,1000,2000 ng/ml, become series standard bent
Line sample.
Precision draws the μ l of standard curve sample 100, in being placed in the centrifuge tube of 1.5 ml, adds sodium citrate buffer solution 100
After μ l and the μ l of inner mark solution 10, the s of vortex 10 are mixed, add 500 μ l ethyl acetate, vortex to vibrate 1 min, stand 5 min,
15000 r/min is centrifuged 10 min;The μ l of clear liquid 400 are sucted in another clean 1. 5 ml centrifuge tubes, in vacuum drying
Volatilize in device, the residue μ l of mobile phase 100 redissolve, vortex mixes 1 min, 15 000 r/min is centrifuged 5 min, obtains for examination
Product solution.
（2）Precision draws the μ L sample introductions of need testing solution 80, and using following chromatographic condition eluting is carried out：
Chromatographic column BETASIL C18 chromatographic columns (4.6 mm × 150 mm, 5 m; Thermo, USA)；
Mobile phase is：Methanol：0.1% formic acid water=70：30（v/v）；
The mLmin of flow velocity 0.5-1；The μ L of sample size 20；25 DEG C of column temperature；MRM patterns：Thalidomide：m/z 259.03→m/z
84.13；m/z 259.03→m/z 186.05；Umbelliferone（Umbelliferone）：m/z 163.01→m/z 107.17.
As a result it is as shown in Figure 1.
（3）LC-MS/MS analyses are carried out, with the peak area of the Thalidomide of variable concentrations and the peak of internal standard umbelliferone
Area ratio Y is vertical coordinate, and rectilinear regression is carried out as abscissa with the blood drug level C of Thalidomide, obtains regression equation and R2。
In terms of signal to noise ratio S/N=3, the minimal detectable concentration of the method is obtained.
Standard curve result is as shown in Figure 2.
3rd, sample detection
（1）Precision is drawn and takes the μ l of the plasma sample after Thalidomide 100, in being placed in the centrifuge tube of 1.5 ml, adds Fructus Citri Limoniae
After the μ l of sour sodium buffer 100 and the μ l of inner mark solution 10, the s of vortex 10 are mixed, 500 μ l ethyl acetate, vortex vibration 1 are added
Min, stands 5 min, and 15 000 r/min is centrifuged 10 min;Suct the μ l of clear liquid 400 to be centrifuged in another clean 1. 5 ml
Guan Zhong, volatilizes in vacuum desiccator, residue with the μ l of mobile phase 100 redissolve, vortex mix 1 min, 15 000 r/min from
The min of the heart 5, takes the μ l of supernatant 80 and adds sample injection bottle, the μ l of sample introduction 10.
（2）Standard curve is substituted into the ratio Y of interior target peak area with the peak area of Thalidomide and calculates Thalidomide
Blood drug level C.
The sample chromatogram result of the LC-MS/MS methods of foundation is as shown in Figure 3.
The mark-on sample detection of embodiment 2
1st, spiked plasma Sample pretreatment
（1）From healthy volunteer's venous blood collection.Blood sample is placed in heparinization EP pipe, and the rpm of whole blood Jing 4000 are centrifuged 5 min and inhale
Upper plasma is taken, i.e., blank human plasma, by 100 L subpackages after -80 DEG C of storages.
Blank human plasma will be added outside Thalidomide, obtain the mark-on that Thalidomide concentration is 2,5,100,1600 ng/mL
Plasma sample.
（2）The L of spiked plasma sample 100 is taken, after being processed according to the Sample pretreatment of embodiment 1, the L of supernatant 80 shiftings is taken
In entering sample injection bottle.
2nd, spiked plasma pattern detection
The L of sample introduction 10 carries out UPLC-MS/MS analyses, and condition is with embodiment 1.Calculating plasma sample concentration according to standard curve is
2.1 ± 0.3,5.2 ± 0.5,107.8 ± 3.6,1654.7 ± 31.0ng/mL, wherein 100ng/mL sample chromatograms such as Fig. 4 institutes
Show.
Show that this assay method can accurately determine the concentration of Thalidomide in analysis blood plasma very much, and it is to be measured in chromatogram
Thing and internal standard peak shape are smooth symmetrical, and noiseless peak, chromatogram is reliable and stable, and method is efficient, stable, can well meet Sha Lidu
The needs of amine pharmcokinetic evaluation.
The pattern detection of embodiment 3
1st, patients with inflammatory bowel disease takes internal Thalidomide concentration after various dose Thalidomide tablet 12h
（1）Patients with inflammatory bowel disease takes venous blood collection about 2mL after various dose Thalidomide tablet 12h.Blood sample is placed in liver
In elementization EP pipes, the rpm of whole blood Jing 4000 are centrifuged 5 min and draw upper plasma, store to survey after -80 DEG C by 100 L subpackages
It is fixed.
（2）The L of human plasma sample 100, with the Sample pretreatment method described in embodiment 1 pre-treatment is carried out, and takes the L of supernatant 80
In moving into sample injection bottle.
2nd, patients with inflammatory bowel disease takes concentration studies plasma sample detection after various dose Thalidomide tablet 12h
The L of sample introduction 10 carries out UPLC-MS/MS analyses, and condition calculates plasma sample concentration with embodiment 1 according to standard curve.
As a result show, 40 patients with inflammatory bowel disease take concentration such as Fig. 5 institutes after various dose Thalidomide tablet 12h
Show.
Claims (10)
1. a kind of method that LC-MS/MS methods detect Thalidomide in blood plasma, it is characterised in that comprise the steps：Precision is measured
Blank plasma, adds a series of Thalidomide standard substance standard working solutions, adds sodium citrate buffer solution and internal standard umbrella shape to spend interior
Ester standard substance standard working solution, using liquid-liquid extraction method pre-treatment after, be analyzed using LC-MS/MS, obtain various kinds true qualities
Spectrogram, with determinand and internal standard peak area ratio as abscissa, by vertical coordinate of testing concentration standard curve is set up；Then it is accurate
Amount test plasma, adds equal-volume sodium citrate buffer solution, adds internal standard umbelliferone standard working solution, is extracted using liquid liquid
After taking method pre-treatment, LC-MS/MS analyses are carried out, obtain the chromatogram of each sample, using standard curve sample blood plasma is calculated
Concentration.
2. method according to claim 1, it is characterised in that comprise the steps：
S1. standard working solution is prepared
Precision weighs Thalidomide and internal standard umbelliferone powder, dissolves and be diluted to standard working solution with lysate respectively；
The lysate is the mixed solution of methanol, acetonitrile and formic acid；
S2. standard curve is set up
Precision measures blank plasma, adds a series of Thalidomide standard working solutions, adds sodium citrate buffer solution and internal standard umbrella
Shape flower lactone standard working solution, using liquid-liquid extraction method pre-treatment, is analyzed afterwards using LC-MS/MS, obtains various kinds true qualities
Spectrogram, with determinand and internal standard peak area ratio as abscissa, by vertical coordinate of testing concentration standard curve is set up；
S3. testing sample detection
S31. sample to be tested blood plasma pre-treatment：Precision amount test plasma, adds equal-volume sodium citrate buffer solution, adds internal standard
Umbelliferone standard working solution, using liquid-liquid extraction method pre-treatment；
S32. it is analyzed using LC-MS/MS, obtains the chromatogram of each sample, using standard curve sample blood plasma is calculated
Concentration.
3. method according to claim 2, it is characterised in that methanol, acetonitrile and formic acid in lysate described in step S1
Volume ratio is 45～55：44～54：1.
4. method according to claim 2, it is characterised in that liquid-liquid extraction method pre-treatment described in step S2 or S31
Agents useful for same is ethyl acetate.
5. method according to claim 3, it is characterised in that the concrete grammar of the liquid-liquid extraction method pre-treatment is：
Sample is added after sodium citrate buffer solution and internal standard umbelliferone standard working solution, after vortex is mixed, adds 2～2.5 times of bodies
Long-pending ethyl acetate, vortex vibration, after standing 3～8min, centrifuging and taking supernatant is volatilized in vacuum desiccator, residue stream
It is dynamic mutually to redissolve, after vortex mixing, centrifuging and taking supernatant, as need testing solution, for the analysis of LC-MS/MS sample introductions.
6. method according to claim 2, it is characterised in that in LC-MS/MS analysis methods, using APCI source ions
Change；The quantitative daughter ion of Thalidomide is 186.1 m/z, and qualitative daughter ion is 84.1 m/z, and interior scalar quantity daughter ion is 107.1
m/z。
7. method according to claim 2, it is characterised in that the volume of sodium citrate buffer solution described in step S2 is blood plasma
With the summation of Thalidomide standard working solution, volume and the Thalidomide standard work of the internal standard umbelliferone standard working solution
The volume for making liquid is identical.
8. method according to claim 2, it is characterised in that the chromatographic condition flowing of LC-MS/MS described in step S2 or S3
Mutually it is set as：Methanol：Volume ratio=70 of 0.1% formic acid water：30.
9. method according to claim 2, it is characterised in that the chromatographic condition of LC-MS/MS is described in step S2 or S3：
The mLmin of flow velocity 0.5-1；The μ L of sample size 20；25 DEG C of column temperature；MRM patterns：Thalidomide：m/z 259.03→m/z
84.13；m/z 259.03→m/z 186.05；Umbelliferone（Umbelliferone）：m/z 163.01→m/z 107.17.
10. method according to claim 2, it is characterised in that the chromatographic column of LC-MS/MS is described in step S2 or S3
BETASIL C18 chromatographic columns.
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