CN103454360A - Ultrafiltration and UPLC-MS/MS (ultra-high performance liquid chromatography tandem mass spectrometry) method for measuring concentration of free docetaxel in human plasma - Google Patents
Ultrafiltration and UPLC-MS/MS (ultra-high performance liquid chromatography tandem mass spectrometry) method for measuring concentration of free docetaxel in human plasma Download PDFInfo
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Abstract
The invention relates to an ultrafiltration and UPLC-MS/MS (ultra-high performance liquid chromatography tandem mass spectrometry) method for measuring concentration of free docetaxel in human plasma and provides a method for measuring the concentration of the free docetaxel in the plasma after docetaxel lipid microsphere injection. The method comprises an ultrafiltration (UF) step and a UPLC-MS/MS analysis step. The UF-UPLC-MS/MS method which is high in sensitivity and specificity and good in reproducibility is established on the premise that the balance of a combination medicine-free medicine in the plasma is not damaged. The method used for measuring the concentration of the free medicine and established for first time meets the biological sample analysis requirements of Guide for the Research of Chemical Drug and Clinical Pharmacokinetics issued by CFDA in 2005 in accuracy, precision, specificity, stability, extracting recovery rate and matrix effect.
Description
Technical field
The present invention relates to the determination method of free docetaxel concentration in blood plasma, belong to analysis technical field.Method of the present invention adopts ultrafiltration combined U PLC-MS/MS to be measured free docetaxel concentration in blood plasma.The present invention can be used for the mensuration of free docetaxel concentration after patient with advanced cancer venoclysis docetaxel lipide microsphere injection.
Background technology
Docetaxel is water-soluble hardly, and clinical docetaxel injecta is usingd Tween 80 as solubilizer as taxotere, when increasing solubleness, causes bad reaction, comprises serious allergic reaction, fluid retention etc.And the docetaxel lipide microsphere injection containing organic solvent with Tween 80, significantly reduced bone marrow toxicity, avoided the direct of medicine and blood vessel contact and can provide essential fatty acid and energy for the patient with severe symptoms.
What prior art detected mostly for the method for measuring the docetaxel drug concentration is total docetaxel concentration.As everyone knows, in blood plasma, free medicine can pass through cell membrane, arrives target site performance drug effect, directly related with curative effect of medication or toxicity.Therefore, free docetaxel drug concentration after detection venoclysis docetaxel lipide microsphere injection, but not medicine that be combined with plasma proteins or the lipid microsphere parcel has larger clinical meaning.
Quantitatively detect in conjunction with or the drug concentration of free taxanes, mainly adopt ultrafiltration, equilibrium dialysis and supercentrifugal process etc.Yet, long (the 8-24h for example of equilibrium dialysis equilibration time, 64h even), there is dilution effect and need radioactive label (referring to such as people such as A.Sparreboom, Cancer Res.59 (1999) 1454.), supercentrifugal process needs the low and poor repeatability of special equipment, sensitivity.
Analysis for the docetaxel free drug is less, the people such as W.J.Loos (Clin.Pharmac01.Ther.74 (2003) 364.) adopt equilibrium dialysis to study under Tween 80 exists free docetaxel in blood plasma, their method needs balance 48h, and result shows that Tween 80 significantly disturbs the concentration of free docetaxel in blood plasma.The people such as M.R.Acharya (Anal.Biochem.331 (2004) 192.) disclose the equilibrium dialysis that adopts the 4h equilibration time.
In order to obtain enough sensitivity, said method all need to adopt the radiopharmaceutical mark (
3and the equilibration time that equilibrium dialysis need to be very long H) and detecting instrument (liquid scintillation instrument).
Not yet find the method without free docetaxel concentration determination after radioactive label mensuration patient with advanced cancer venoclysis docetaxel lipide microsphere injection in prior art.
For meeting the requirement of clinical detection, this area is badly in need of without special equipment requirement, high flux, the rear free docetaxel method for measurement of concentration of sample demand docetaxel lipid microsphere injection few, easily and fast.
Summary of the invention
Directly measure the method for free docetaxel concentration after the invention provides the injection of docetaxel lipid microsphere.Method of the present invention is highly sensitive, specificity strong, quick, favorable reproducibility, and does not need radioactive label and relevant specific apparatus, free docetaxel concentration after therefore being suitable for clinical measurement and monitoring the injection of docetaxel lipid microsphere.
Therefore, one of purpose of the present invention is to provide after a kind of tumor patient venoclysis docetaxel lipide microsphere injection the method for measuring free docetaxel concentration in blood plasma.Free docetaxel concentration in blood plasma after this method employing ultrafiltration associating Ultra Performance Liquid Chromatography tandem mass spectrometry (UF-UPLC-MS/MS) detection patient with advanced cancer venoclysis docetaxel lipide microsphere injection.Under the prerequisite of the present invention's combination-free drug balance in not destroying blood plasma, set up highly sensitive, specificity strong, fast, the UF-UPLC-MS/MS method of favorable reproducibility.
In the method for the invention, in liquid-phase condition, mobile phase preferably adopts 0.2% formic acid-5mM ammonium acetate (water)-0.2% formic acid acetonitrile (organic phase).Add formic acid can promote the analyte ionization, improve the sensitivity detected.Adding ammonium acetate is to have utilized electrolyte effect, has not only increased the ionization effect of determinand but also has been conducive to eliminate the conditions of streaking of chromatographic peak.In addition, adopt in the method for the invention efficient ACQUITY UPLC BEH C
18chromatographic column (50mm * 2.1mm I.D., particle diameter is 1.7 μ m), improved separation efficiency, realized that be only 2.5min the analysis time of each sample, significantly increased analysis throughput, improved analysis speed, is conducive to the express-analysis of clinical sample in enormous quantities.Method of the present invention adopts the QTRAP5500 mass spectrometer system of high sensitivity, supper-fast sweep velocity, and quantitative detectability is low to moderate 0.2ng/mL.
Detecting free drug concentration in blood plasma under the prerequisite of not destroying the normal plasma protein binding rate is the key in quantitative test.For this reason, in test, adopt the method for ultrafiltration to realize separating of free drug and bound drug, prepare 4 concentration levels blood plasma Quality Control sample (200,500,1000,5000ng/mL) analyze.Test findings shows, under the condition of the inventive method, in blood plasma, free medicine mark is consistent substantially, and the prompting test operation does not destroy the balance of combination-free drug, and the drug concentration detected is the level of the interior free drug of antimer truly.
In the method for the invention, adopt sample volume still less, for example 450 μ L VS2.0mL than bibliographical information.Plasma sample is in 37 ℃ of balance 1h, accurate draw 450 μ L plasma samples join super filter tube upper chamber and 37 ℃ centrifugal, gained ultrafiltrate volume can meet the needs of concentration analysis.Method of the present invention is verified, under condition of the present invention, in quantitative test blood plasma, the free required sample volume of docetaxel concentration, significantly lower than the plasma sample volume (as 2mL) of bibliographical information, therefore is particularly suitable for the purpose of plasma sample measure analysis less in clinical testing.
Reported in prior art under low centrifugal force (such as 1500g) and carried out ultrafiltration centrifugal (referring to people such as H.van den Bongard, Anal.Biochem.324 (2004) 11.).Yet the present invention finds preferably for example to use, than high centrifugal force, more than 2000g, as 2000-10000g (comprising for example 2500-9000g, 3000-8000g, 4000-7000g, 4500-6500g etc.) carries out surprisingly.Centrifugation time can be 0.5-2h (comprising for example 0.5-1.75h, 0.8-1.5h, 0.9-1.25h etc.).Centrifuging temperature can carry out under 25-37 ℃.Under condition of the present invention, we find that higher centrifugal force does not affect free drug concentration and unbound fraction.The determination method that the present invention sets up all reaches the analysis requirement of CFDA to biological sample at aspects such as accuracy, precision, specificity, stability, extraction recovery and matrix effects, and has significantly shortened analysis time.Method of the present invention adopts the accurate upper chamber that 450 μ L plasma samples join super filter tube of drawing, in 37 ℃ of balance 1h, and 6000g, 37 ℃ of centrifugal 1h.After the liquid-liquid extraction of 3mL t-butyl methyl ether, 40 ℃ of nitrogen flow down and volatilize, and draw 5 μ L after redissolving and carry out the UPLC-MS/MS analysis.
The pretreatment process of plasma sample is to obtain highly sensitive key in UPLC-MS/MS.In the present invention, can adopt precipitation of protein, solid phase extraction and liquid-liquid extraction method to be processed plasma sample.Yet method of the present invention preferably adopts liquid-liquid extraction method to carry out the pre-service of plasma sample.Data provided by the invention show to adopt that liquid-liquid extraction method is easy, sensitive, extraction recovery is high, and liquid-liquid extraction method meets the requirement to measuring in test fully.
Therefore, the invention provides the method for measuring free docetaxel concentration in the rear blood plasma of docetaxel lipid microsphere injection, described method comprises ultrafiltration step and Ultra Performance Liquid Chromatography tandem mass spectrum (UPLC-MS/MS) analytical procedure.Method of the present invention can be used for analyzing the concentration of mammal as free docetaxel in rat, mouse, human plasma.
In the preferred embodiment of the inventive method, ultrafiltration step can adopt the sample of 300 μ L-1.8mL to carry out, and for example adopts 320 μ L-1.5mL, 360 μ L-1.5mL, and 380 μ L-1.2mL, 400 μ L-1.0mL, the sample of 420 μ L-0.8mL carries out.
In the preferred embodiment of the inventive method, ultrafiltration step is included in 2000-10000g, for example, at 2500-9000g, and 3000-8000g, 4000-7000g, 4500-6500g carries out centrifugal step.
In the preferred embodiment of the inventive method, ultrafiltration step comprises and carries out 0.5-2h, 0.75-1.75h for example, and 0.8-1.5h, 0.9-1.25h is centrifugal.
In the preferred embodiment of the inventive method, ultrafiltration step is included in 4 ℃, 25 ℃ and 37 ℃, preferably at 37 ℃, carries out centrifugal step.
In the preferred embodiment of the inventive method, before described Ultra Performance Liquid Chromatography Tandem Mass Spectrometry Analysis, by precipitation of protein, solid phase extraction and liquid-liquid extraction method, plasma sample is processed, preferably by liquid-liquid extraction method, plasma sample is processed.
In the preferred embodiment of the inventive method, liquid-liquid extraction method adopts t-butyl methyl ether to carry out.
In the preferred embodiment of the inventive method, the Ultra Performance Liquid Chromatography Tandem Mass Spectrometry Analysis adopts 0.2% formic acid-5mM ammonium acetate (water)-0.2% formic acid acetonitrile (organic phase) to carry out gradient elution for mobile phase.
In the preferred embodiment of the inventive method, the Ultra Performance Liquid Chromatography Tandem Mass Spectrometry Analysis adopts ACQUITY UPLC BEH C18 chromatographic column to carry out.
In the preferred embodiment of the inventive method, the Ultra Performance Liquid Chromatography Tandem Mass Spectrometry Analysis comprises interior mark taxol.
The ultrafiltration that the present invention sets up-Ultra Performance Liquid Chromatography tandem mass spectrometry all reaches the analysis requirement of CFDA to biological sample at aspects such as accuracy, precision, specificity, stability, extraction recovery and matrix effects.What particularly point out is, the plasma sample volume of this assay method utilization is 450 μ L, be low to moderate 2.5min analysis time, significantly lower than volume and the time of bibliographical information, make less sample demand and relatively short analysis time the present invention be applicable to high flux and detect after venoclysis docetaxel lipide microsphere injection the concentration of free docetaxel in blood plasma.
The method that the present invention sets up first can be used for after late tumor patient venoclysis docetaxel lipide microsphere injection the mensuration of free docetaxel concentration in blood plasma, for the relation of better understanding between medicine generation-drug effect provides foundation, also for the free drug concentration detection of the novel form of other lipid microsphere forms in the future, provide reference.
The accompanying drawing explanation
Fig. 1: the free drug mark of docetaxel under condition of different temperatures.
Fig. 2: docetaxel free drug mark during different centrifugal force.
Fig. 3: the specificity of the inventive method and specificity.
Fig. 4: docetaxel free drug concentration and the always comparison of drug concentration.
Fig. 5: the scanning of the mass spectrum figure of docetaxel and interior mark taxol.
Embodiment
For more clearly the present invention will be described, below by concrete embodiment, the specific embodiment of the present invention is described in more detail.But should be appreciated that, the concrete embodiment of the following stated only carries out exemplary illustration for the present invention, but not carry out any character restriction for the present invention, and wherein material therefor, reagent, instrument and operating conditions are only representational, it is not limited to cited situation.The person of ordinary skill in the field can make change and the improvement that does not break away from the protection domain that the claims in the present invention limit to the present invention by reading following explanation, these changes and improving also in the present invention's scope required for protection.
1 instrument, material and reagent
1.1 instrument Waters Ultra Performance Liquid Chromatography instrument series connection QTRAP5500 mass detector, U.S. Waters company and AB Sciex company; Nitrogen evaporator, Hangzhou Austria fills limit company; MillQ-Direct8 ultrapure water system, U.S. Millipore Corp.; Fixing corner hydro-extractor, U.S. Thermo Scientific company.
1.2 sample and reagent docetaxel (purity>98%), taxol (purity>98%), be purchased from Nat'l Pharmaceutical & Biological Products Control Institute; HPLC level t-butyl methyl ether, methyl alcohol, acetonitrile all are purchased from U.S. Fisher Scientific company;
ultra-0.5 super filter tube (molecular cut off is 10KDa), be purchased from U.S. Millipore Corp..
2 experimental sections
2.1 the ultrafiltration condition analysis is according to total drug concentration scope in blood plasma after clinical vein infusion docetaxel lipide microsphere injection, the blood plasma quality-control sample (200,500,1000 of at least 3 concentration levels of preparation, 5000ng/mL), for analyzing ultra-filtration process.When selecting centrifuging temperature, we have investigated simulating blood plasma sample plasma free medicine mark when 4 ℃, 25 ℃ and 37 ℃, also investigated different centrifugal force (2000,6000 and 10000g), different centrifugation time (the 30 and 60min) impact on unbound fraction simultaneously.
2.2 the 7mL centrifuge tube is got in the plasma sample pre-service, adds 50ng/mL inner mark solution 10 μ L and 20 μ L working fluids, adds the ultrafiltrate plasma sample 200 μ L that remove plasma proteins through ultrafiltration, vortex 1min, mix.Then add t-butyl methyl ether 3mL, vortex concussion 10min, the centrifugal 10min of 4000rpm.Get upper organic phase 2mL, be transferred in clean EP pipe, flow down and volatilize in 40 ℃ of nitrogen, residue redissolves with 200 μ L methyl alcohol, vortex concussion 1min, in the centrifugal 10min of 12000rpm, remove residual impurity, draw 50 μ L supernatants in sample bottle, get supernatant 5 μ L sample introductions and carry out the UPLC-MS/MS analysis, the peak area of recording quality chromatogram and compound, adopt internal standard method to calculate the concentration of docetaxel.
2.3UPLC-MS/MS condition
Chromatographic condition: adopt efficient ACQUITYUPLC BEH C18 chromatographic column (50mm * 2.1mm I.D., particle diameter is 1.7 μ m), column temperature is 35 ℃.Mobile phase is A phase (water contains 0.2% formic acid and 5mM ammonium acetate): B phase (acetonitrile contains 0.2% formic acid)=90: 10 (v: v).Flow velocity is 0.3mL/min, and sample size is 5 μ L.Adopt gradient elution, be 2.5min analysis time.
Mass spectrum condition: adopt electric spray ion source (Electrospray ionization, ESI), at positive ion electrospray under pattern, select multiple-reaction monitoring pattern (multiple reaction monitoring, MRM) scanning of the mass spectrum mode is measured, be 100ms the sweep time of each MRM passage, the mother of docetaxel and interior mark taxol, the right mass-to-charge ratio of daughter ion are respectively: m/z808.8 → 527.1 (docetaxel) and m/z854.6 → 285.9 (taxols, IS), retention time is respectively 1.32min, 1.32min.Scanning of the mass spectrum figure See Figure to docetaxel and interior mark taxol.
3 results
3.1 the optimization of ultrafiltration condition is applicable to separate bound drug and free drug in order to guarantee hyperfiltration process, the present invention compares (table 1) by the unbound fraction of blood plasma Quality Control, and the condition of ultrafiltration is analyzed.Wherein, when plasma drug level is 10000ng/mL, free drug concentration exceeds the typical curve upper limit, so finally the concentration of definite blood plasma quality-control sample is respectively 200,500,1000 and 5000 ng/mL.Different ultrafiltration temperature are shown in Fig. 1 to the impact of unbound fraction, along with the rising unbound fraction of temperature presents rising trend, in order not destroy the balance of free-bound drug in body, under finally adopting 37 ℃, carry out centrifugal, because this temperature is normal human's temperature, better simulated the time of day of human body.We are also investigated time, the centrifugal force of ultrafiltration, the results are shown in Table 2 and Fig. 2, and preferably the ultra-filtration process of sample is at 6000g, centrifugal 60min.Hydrophobic drug is the key factor of hyperfiltration process to the non-specific binding of ultra filtration membrane, the quality-control sample that adopts methyl alcohol to prepare basic, normal, high concentration in the present invention carries out the investigation of non-specific binding, and result shows that under this test condition non-specific binding do not disturb the mensuration of unknown sample.
The blood plasma Quality Control concentration analysis of table 1 ultrafiltration condition
The ultrafiltration time series analysis of table 2 ultrafiltration condition
3.2 methodology checking
3.2.1 in specificity this method, determinand and interior target specificity contrast and are estimated with the blank plasma ultrafiltrate operated with method with typical curve least concentration point.The chromatogram of patient's blood plasma ultrafiltrate is shown in Fig. 3 when two blank plasma ultrafiltrates, blank plasma ultrafiltrate add interior mark taxol (50ng/mL), low lower limit of quantitation (LLOQ, 0.5ng/mL) and after venoclysis docetaxel lipide microsphere injection.Above result shows, the specificity of method is good, the not detection of interference medicament concentration of endogenous material in the blank plasma ultrafiltrate, docetaxel and interior target retention time 1.32min.Fig. 3 has shown specificity and the specificity of method.
3.2.2 add docetaxel working fluid 20 μ L in linear and sensitivity 180 μ L human normal plasma ultrafiltrates, add inner mark solution (50ng/mL) 10 μ L, be mixed with that to be equivalent to concentration be 0.5,1,2,10,20,100 and the sample of 200ng/mL, carry out the UPLC-MS/MS analysis under 2.3, with weighting (W=1/X
2) least square method returns calculating, adopts internal standard method, tries to achieve linear regression equation, is typical curve.The range of linearity of this method is 0.5～200ng/mL, correlation coefficient r
20.99.This method lowest detectable limit and minimum lower limit of quantitation are respectively 0.2ng/mL (S/N=3) and 0.5ng/mL (S/N=10).
3.2.3 precision and accuracy are according to aforesaid operations, the quality-control sample for preparing basic, normal, high 3 concentration of docetaxel (1.5,20,150ng/mL), parallel 5 sample analysis of each concentration, 3 batches of METHOD FOR CONTINUOUS DETERMINATION, computing method batch in, official written reply precision (RSD%) and accuracy (RE%), analysis result is as table 3.It is as shown in the table, in batch, the low Quality Control concentration of official written reply precision accuracy all within ± 20%, middle high Quality Control concentration all, within ± 15%, illustrate that this method has good preci-sion and accuracy, meets the requirement of biological sample quantitative analysis.
Claims (10)
1. the method for the docetaxel concentration of dissociating in blood plasma after mensuration venoclysis docetaxel lipide microsphere injection, described method comprises ultrafiltration (UF) step and Ultra Performance Liquid Chromatography tandem mass spectrum (UPLC-MS/MS) analytical procedure.
2. method claimed in claim 1, wherein said ultrafiltration step adopts the sample of 300 μ l-1.8ml to carry out, and for example adopts 320 μ L-1.5mL, 360 μ L-1.5mL, 380 μ L-1.2mL, 400 μ L-1.0mL, the sample of 420 μ L-0.8mL carries out.
3. the described method of claim 1 or 2, wherein said ultrafiltration step is included in 2000-10000g, for example, at 2500-9000g, 3000-8000g, 4000-7000g, 4500-6500g carries out centrifugal step.
4. the described method of any one in claim 1-3, wherein said ultrafiltration step comprises and carries out 0.5-2h, 0.75-1.75h for example, 0.8-1.5h, 0.9-1.25h is centrifugal.
5. the described method of any one in claim 1-4, wherein said ultrafiltration step is included in 4 ℃, 25 ℃ and 37 ℃, preferably at 37 ℃, carries out centrifugal step.
6. the described method of any one in claim 1-5, wherein before described Ultra Performance Liquid Chromatography Tandem Mass Spectrometry Analysis, by precipitation of protein, solid phase extraction and liquid-liquid extraction method, plasma sample is processed, preferably by liquid-liquid extraction method, plasma sample is processed.
7. method claimed in claim 6, wherein said liquid-liquid extraction method adopts t-butyl methyl ether to carry out.
8. the described method of any one in claim 1-7, wherein said Ultra Performance Liquid Chromatography Tandem Mass Spectrometry Analysis adopts 0.2% formic acid-5mM ammonium acetate (water)-0.2% formic acid acetonitrile (organic phase) to carry out gradient elution for mobile phase.
9. the described method of any one in claim 1-8, wherein said Ultra Performance Liquid Chromatography Tandem Mass Spectrometry Analysis adopts ACQUITY UPLC BEH C18 chromatographic column to carry out.
10. the described method of any one in claim 1-9, in wherein said Ultra Performance Liquid Chromatography Tandem Mass Spectrometry Analysis, comprise interior mark taxol.
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