CN109444301A - A kind of method of general reed Ka Bili concentration in measurement blood plasma - Google Patents
A kind of method of general reed Ka Bili concentration in measurement blood plasma Download PDFInfo
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- CN109444301A CN109444301A CN201811551668.XA CN201811551668A CN109444301A CN 109444301 A CN109444301 A CN 109444301A CN 201811551668 A CN201811551668 A CN 201811551668A CN 109444301 A CN109444301 A CN 109444301A
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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
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
Abstract
The invention discloses a kind of methods of general reed Ka Bili concentration in measurement blood plasma, using LC-MS system measurement, first take sample to be tested, a certain amount of organic solvent is added to be extracted, after pretreatment, through chromatography post separation, detected with mass detector, the method of the present invention quickly, it is accurate, high sensitivity, easy to operate, be suitable for measuring the concentration of general reed Ka Bili in blood plasma.
Description
Technical field
The invention belongs to Pharmaceutical Analysis technical fields, are related to the analysis determining method of internal drug, and in particular to a kind of survey
Determine the method for general reed Ka Bili concentration in blood plasma.
Background technique
The general reed Ka Bili of succinic acid (Prucalopride succinate) is benzofurans Prokinetic drug, is special
Property 5-HT4 receptor full agonists, have more highly selective and specific 5-HT4 receptor acting, increase cholinergic neurotransmitter
Release, stimulation enterocinesia reflects, enhances colon contraction and proximal colonic transmission, be capable of the disease of effectively relief of constipation patient
Shape is mainly used for treating the gastrointestinal motility inability and Pseudo-Obstruction of various constipation and operation.
After the oral general reed Ka Bili of succinic acid, succinic acid is sloughed in vivo, is transformed into general reed Ka Bili and is absorbed into blood.
The present invention, which establishes one, has highly sensitive and highly selective liquid chromatography-tandem mass spectrometry method (LC-MS/MS), is used for
The concentration of general reed Ka Bili in blood plasma is measured, and general reed Ka Bili is carried out in the intracorporal drug metabolism situation of people by this method
Pilot study.
Summary of the invention
Technical problem to be solved by the invention is to provide general reed Ka Bili concentration in a kind of precise and high efficiency measurement blood plasma
Method.
In order to solve the above technical problems, The technical solution adopted by the invention is as follows:
The method of general reed Ka Bili concentration, is examined after plasma sample is preprocessed through LC-MS system in a kind of measurement blood plasma
Its concentration is surveyed, specific method includes the following steps:
(1) plasma sample pre-processes: taking plasma sample, the general reed Ka Bili-of Isotopic Internal Standard is added13CD3And sodium hydroxide
Solution is added ethyl acetate extraction, draws upper organic phase, and centrifugal concentrating volatilizes at 40 DEG C, and it is water-soluble that 80% (v/v) methanol is added
Liquid dissolution, takes supernatant after centrifugation；
(2) the pretreated plasma sample of step (1) is subjected to liquid chromatogram separation: chromatographic column Agilent
ZORBAXSB-C18,3.0 × 100mm, 3.5 μm；Mobile phase: volume ratio is the methanol and 1mmolL of 80:20-1Ammonium acetate is water-soluble
Liquid isocratic elution；Flow velocity: 400 μ Lmin-1；Column temperature: 35 DEG C；Sample volume: 4 μ L；Analysis time: 5min；
(3) mass spectroscopy: ion source is electro-spray ionization ionization source ESI；Ion detection mode is multiple-reaction monitoring；From
Sub- polarity is cation；Ion source voltage IS:5500V；TEM:500 DEG C of ion source temperature；Collision gas CAD:10psi；Gas curtain gas
CUR:25psi；Ion source Gas1:60psi；Ion source Gas2:65psi；Collision cell entrance potential: 10V；Collision cell outlet electricity
Pressure: 14V；The ion selector channel of test object: general reed Ka Bili, [M+H]+, m/z 368.4/196.0, DP 96V, CE
40eV；The general reed Ka Bili-of Isotopic Internal Standard13CD3, [M+H]+, m/z 374.4/198.0, DP91V, CE 43eV；
(4) it calculates: internal standard method is used, with general reed Ka Bili and the general reed Ka Bili-of Isotopic Internal Standard13CD3Peak area ratio
Value substitutes into calibration curve equation and calculates general reed Ka Bili concentration.
In step (1), accurate in 10mL teat glass that plasma sample 0.4mL is added, 10ngmL is added in precision-1Same position
The plain general reed Ka Bili-of internal standard13CD3Solution 100 μ L, 1mol.L-180 μ L of sodium hydroxide, be added ethyl acetate 4mL, vortex oscillation
10min, 2000rmin-1It is centrifuged 10min, draws upper organic phase 3mL, 40 DEG C of centrifugal concentratings volatilize, and 80% (v/v) first is added
200 μ L of alcohol solution redissolves, and vortex 1min, 12000g are centrifuged 5min, and 150 μ L of Aspirate supernatant is analyzed.
Wherein, the blood plasma is the blood plasma after the oral general reed Ka Bili of succinic acid.The method of the present invention emphasis is protection mouth
After taking the general reed Ka Bili of succinic acid, the detection method of general reed Ka Bili in blood plasma, thus to study the internal generation of general reed Ka Bili
It thanks and lays the foundation.
Wherein, the blood plasma is the blood plasma of human or animal.
The utility model has the advantages that the method for the present invention has the advantage that
(1) preprocess method is easy: organic solvent liquid-liquid extraction method is suitable for conventional determining；
(2) specificity is strong: using ZOBAX SB-C18 chromatographic column as stationary phase, first alcohol and water (1mmol.L-1Ammoniom-Acetate)
Mixed liquor as mobile phase, isocratic elution, pulika must benefit and the general reed Ka Bili-of Isotopic Internal Standard13CD3Retention time is
3.6min or so, 5min complete measurement, and endogenous material does not interfere the measurement of the two；
(3) high sensitivity: blood plasma is minimum to be quantitatively limited to 0.05896ngmL-1；
(4) the method for the present invention quickly, it is accurate, high sensitivity, easy to operate, be pulika must the clinical blood concentration of benefit survey
It is fixed that foundation is provided, serve the clinical application of drug.The plasma standard curve linear range of this method be 0.05896~
7.547ng·mL-1, in batch and betweenrun precision CV is respectively less than 10%.
Detailed description of the invention
Fig. 1 is general reed Ka Bili (A) and the general reed Ka Bili-of Isotopic Internal Standard13CD3(B) chemical structure schematic diagram；
Fig. 2 is general reed Ka Bili (A) and the general reed Ka Bili-of Isotopic Internal Standard13CD3(B) second order ms figure；
Fig. 3 is that the LC-MS/MS of all kinds of representative samples schemes, and A is blank plasma；B is blood plasma lower limit of quantitation sample；C is low
Concentrations control product solution example；D is low concentration blood plasma quality-control sample；E is that subject takes orally the general reed Ka Bili piece 3h of 2mg succinic acid
(note: left side is general reed Ka Bili ion channel, [M+H] to plasma sample afterwards in figure+, m/z368.4/196.0；Right side is same position
The plain general reed Ka Bili-of internal standard13CD3Ion channel, [M+H]+, m/z 374.4/198.0；Retention time is 3.6min or so).
Specific embodiment
According to following embodiments, the present invention may be better understood.However, as it will be easily appreciated by one skilled in the art that real
It applies content described in example and is merely to illustrate the present invention, without sheet described in detail in claims should will not be limited
Invention.
Embodiment: the measurement of general reed Ka Bili concentration in human plasma.
One, experimental material and instrument
General reed Ka Bili reference substance: it is provided by Jiangsu Ji Chuan medicine company, lot number: 160328；General reed Ka Bili-13CD3Control
Product: it is provided by Stanta Cruz company, lot number: E2517；Test water: ultrapure water；Methanol: chromatographically pure (Merck
Company)；Ethyl acetate: it analyzes pure (Nanjing Chemistry Reagent Co., Ltd.)；Ammonium acetate: chromatographically pure (ACS company)；Hydroxide
Sodium: it analyzes pure (Nanjing Chemistry Reagent Co., Ltd.).
API 4000LC-MS/MS combined instrument (Applied biosystems), chromatographic work station: Analyst 1.6；
Plum Teller MS105 electronic balance (Mei Tele company, Switzerland)；MICRO 17R high speed low temperature centrifugal machine (Thermo company, the U.S.)；
80-4 low speed centrifuge (Changzhou Guohua Electric Appliance Co., Ltd.)；Millipore-Q Advantage A10 ultrapure water machine (France
Millipore company)；CentriVap centrifuge concentrator (Labconco company, the U.S.)；VX-II multitube turbula shaker (Beijing
Ta Jin Science and Technology Ltd.).
Two, liquid matter condition
1. liquid phase chromatogram condition
Chromatographic column: Agilent ZOBAX SB-C18 (3.0 × 100mm, 3.5 μm)；Pre-column: Agilent ZORBAX SB-
C18 (4.6 × 12.5mm, 5 μm)；Mobile phase: methanol-water (i.e. 1mmolL-1Ammonium acetate aqueous solution) 80: 20 (v/v)；Flow velocity:
400μL·min-1；Column temperature: 35 DEG C；Autosampler temperature: 4 DEG C；Sample volume: 4 μ L, analysis time: 5min.
2. Mass Spectrometry Conditions
Ion source is electro-spray ionization ionization source ESI；Ion detection mode is multiple-reaction monitoring；Ion polarity be positive from
Son；Ion source voltage IS:5500V；TEM:500 DEG C of ion source temperature；Collision gas CAD:10psi；Gas curtain gas CUR:25psi；From
Component Gas1:60psi；Ion source Gas2:65psi；Collision cell entrance potential: 10V；Collision cell exit potential: 14V；Detection pair
The ion selector channel of elephant: general reed Ka Bili, [M+H]+, m/z368.4/196.0, DP 96V, CE 40eV；Isotopic Internal Standard is general
Reed Ka Bili-13CD3, [M+H]+, m/z 374.4/198.0, DP 91V, CE 43eV.
Three, experimentation:
1. the preparation of general reed Ka Bili reference substance solution:
The preparation of 1.1 general reed Ka Bili standard curve working solutions
Precision weighs the general reed Ka Bili reference substance 10.69mg of succinic acid in 10mL volumetric flask, with methanol dissolution, constant volume,
It mixes, through salt coefficient, moisture and purity correction, obtaining concentration is 0.8068mgmL-1General reed Ka Bili stock solution, then with first
Alcohol successively dilutes, and being made into concentration is respectively 1.179,2.358,4.717,9.434,18.87,37.74,75.47,150.9ng
mL-1General reed Ka Bili standard curve working solution.
The preparation of 1.2 general reed Ka Bili Quality Control working solutions
Precision weighs the general reed Ka Bili reference substance 10.41mg of succinic acid in 10mL volumetric flask, with methanol dissolution, constant volume,
It mixes, through salt coefficient, moisture and purity correction, obtaining concentration is 0.7856mgmL-1General reed Ka Bili stock solution, then with first
Alcohol successively dilutes, and being made into concentration is respectively 1.179,3.275,14.74,117.9ngmL-1General reed Ka Bili Quality Control work
Liquid.
2. the processing of human plasma sample:
48 women's health subjects take the general reed Ka Bili piece of succinic acid respectively at (24) on an empty stomach or postprandial (24)
(2mg), with 240mL warm water delivery service；0.5,1,1.5,2,2.5,3,4,5,6,8,12,24,48 and before medication and after medication
72 hours acquisition peripheric venous blood 4ml inject in sodium citrate pipe, are centrifuged (3000rmin-1× 10min) obtain blood plasma.Divide and takes
Blood plasma 0.4mL sequentially adds 10ngmL in 10mL teat glass-1Internal standard working solution 100 μ L, 1mol.L-1Hydroxide
Sodium 80 μ L, ethyl acetate 4mL, vortex 10min are sufficiently extracted, 2000rmin-1× 10min centrifugation, Aspirate supernatant
3mL enters in centrifuge concentrator and volatilizes for 40 DEG C, and 80% (v/v) methanol aqueous solution, 200 μ L is added, and is vortexed after mixing 1min, 12000g
× 5min, 4 DEG C of centrifugations, takes 150 μ L of supernatant to carry out LC-MS/MS analysis.
3. specificity:
It takes the people's blank plasma 0.4mL for being not given to the general reed Ka Bili of succinic acid in 10mL glass tube, sequentially adds
Methanol 100 μ L, 1molL-1Sodium hydroxide 80 μ L, ethyl acetate 4mL, vortex 10min sufficiently extracted, 2000r
min-1× 10min centrifugation, Aspirate supernatant 3mL enter in centrifuge concentrator and volatilize for 40 DEG C, and 80% (v/v) methanol aqueous solution is added
200 μ L are vortexed after mixing 1min, 12000g × 5min, and 4 DEG C of centrifugations take 150 μ L of supernatant to carry out LC-MS/MS analysis (see figure
3A)。
Take the people's blank plasma 0.4mL for being not given to the general reed Ka Bili of succinic acid in 10mL glass tube, precision is added
General reed Ka Bili standard curve working solution (1.179ngmL-1) 20 μ L, sequentially add 10ngmL-1100 μ of internal standard working solution
L, 1molL-1Sodium hydroxide 80 μ L, ethyl acetate 4mL, vortex 10min sufficiently extracted, 2000rmin-1×
10min centrifugation, Aspirate supernatant 3mL enter in centrifuge concentrator and volatilize for 40 DEG C, and 80% (v/v) methanol aqueous solution, 200 μ L is added,
It is vortexed after mixing 1min, 12000g × 5min, 4 DEG C of centrifugations take 150 μ L of supernatant to carry out LC-MS/MS analysis (see Fig. 3 B).
Take 1.5mL plastic centrifuge tube precision that the general reed Ka Bili Quality Control working solution (3.275ngmL of low concentration is added-1)20μ
10ngmL is added in L-1Internal standard working solution 100 μ L, 50% methanol (v/v) 80 μ L, vortex 1min, draw 150 μ L carry out LC-
MS/MS analyzes (see Fig. 3 C).
Take the people's blank plasma 0.4mL for being not given to the general reed Ka Bili of succinic acid in 10mL glass tube, precision is added
The general reed Ka Bili Quality Control working solution (3.275ngmL of low concentration-1) 20 μ L, sequentially add 10ngmL-1Internal standard working solution
100 μ L, 1molL-1Sodium hydroxide 80 μ L, ethyl acetate 4mL, vortex 10min sufficiently extracted, 2000rmin-1×
10min centrifugation, Aspirate supernatant 3mL enter in centrifuge concentrator and volatilize for 40 DEG C, and 80% (v/v) methanol aqueous solution, 200 μ L is added,
It is vortexed after mixing 1min, 12000g × 5min, 4 DEG C of centrifugations take 150 μ L of supernatant to carry out LC-MS/MS analysis (see Fig. 3 D).
It takes the human plasma 0.4mL for taking orally the general reed Ka Bili piece of 2mg succinic acid in 10mL glass tube, sequentially adds
10ng·mL-1Internal standard working solution 100 μ L, 1molL-1Sodium hydroxide 80 μ L, ethyl acetate 4mL, vortex 10min are carried out
It sufficiently extracts, 2000rmin-1× 10min centrifugation, Aspirate supernatant 3mL enter in centrifuge concentrator and volatilize for 40 DEG C, are added 80%
(v/v) 200 μ L of methanol aqueous solution is vortexed after mixing 1min, 12000g × 5min, and 4 DEG C of centrifugations take 150 μ L of supernatant to carry out LC-
MS/MS analyzes (see Fig. 3 E).
The results show that plasma sample causes detected components without miscellaneous peak under the conditions of the LC-MS/MS used by this experiment
Interference, general reed Ka Bili and Isotopic Internal Standard retention time are in 3.6min or so.Determinand and Isotopic Internal Standard are not interfere with each other,
Peak shape is good, and baseline is steady.
4. linear test
Human plasma standard curve: taking 10mL teat glass number branch, and the people for being not given to the general reed Ka Bili of succinic acid is added
Blank plasma 0.4mL is separately added into the general 20 μ L of reed Ka Bili standard curve working solution of various concentration, is made into containing general reed Ka Bili
Concentration is respectively 0.05896,0.1179,0.2358,0.4717,0.9434,1.887,3.774,7.547ngmL-1Drug containing
Blood plasma is pressed and is operated under " processing of human plasma sample " item.Calculate the ratio of determinand peak area As and Isotopic Internal Standard peak area Ai
Value f (f=As/Ai) makees blood concentration C with peak area ratio f to return calculating, obtains regression equation: f=(1.22 ± 0.036) C
+ (0.00285 ± 0.00398), r=0.999 ± 0.0015, w=1/C2, n=5, general reed Ka Bili plasma concentration is 0.05896
~7.547ngmL-1Linear relationship is good in range, minimum to be quantitatively limited to 0.05896ngmL-1。
5. accuracy and precision
Preparing according to human plasma standard curve method containing general reed Ka Bili concentration is 0.05896,0.1638,0.7370,
5.896ng·mL-1Lower limit of quantitation and basic, normal, high concentrations Plasma quality-control sample, press " processing of human plasma sample " Xiang Xiacao
Make.3 batches are continuously done, each concentration of every batch of respectively makees 6 parts of samples, calculates determinand peak area As's and Isotopic Internal Standard peak area Ai
Ratio f is substituted into the plasma standard curve on the same day and is acquired determinand measured concentration, by measured concentration calculate batch in, batch between it is accurate
It spends (being indicated with coefficient of variation CV), measured concentration and the ratio that concentration is added are accuracy.The results show that batch in and batch between CV
Respectively less than 10%, accuracy meets 2015 editions pharmacopoeial requirements within the scope of 85%-115%.
6. measurement result
Above-mentioned empty stomach gives general reed Ka Bilida in 24 women's health subject's blood plasma of the general reed Ka Bili piece of succinic acid
Cmax CmaxMean value be 4.269ngmL-1(SD=± 0.7488), 24 for giving the general reed Ka Bili piece of succinic acid after the meal
General reed Ka Bilida Cmax C in women's health subject's blood plasmamaxMean value be 4.192ngmL-1(SD=± 0.6171).
Claims (4)
1. a kind of method of general reed Ka Bili concentration in measurement blood plasma, which is characterized in that through liquid matter after plasma sample is preprocessed
Combined system detects its concentration, and specific method includes the following steps:
(1) plasma sample pre-processes: taking plasma sample, the general reed Ka Bili-of Isotopic Internal Standard is added13CD3And sodium hydroxide solution,
Ethyl acetate extraction is added, draws upper organic phase, centrifugal concentrating volatilizes at 40 DEG C, and it is molten that 80% (v/v) methanol aqueous solution is added
Solution, takes supernatant after centrifugation；
(2) the pretreated plasma sample of step (1) is carried out liquid chromatogram separation: chromatographic column is Agilent ZORBAX SB-
C18,3.0 × 100mm, 3.5 μm；Mobile phase: the methanol and 1mmolL of volume ratio 80: 20-1Ammonium acetate aqueous solution is isocratic to be washed
It is de-；Flow velocity: 400 μ Lmin-1；Column temperature: 35 DEG C；Sample volume: 4 μ L；Analysis time: 5min；
(3) mass spectroscopy: ion source is electro-spray ionization ionization source ESI；Ion detection mode is multiple-reaction monitoring；Ion pole
Property is cation；Ion source voltage IS:5500V；TEM:500 DEG C of ion source temperature；Collision gas CAD:10psi；Gas curtain gas CUR:
25psi；Ion source Gas1:60psi；Ion source Gas2:65psi；Collision cell entrance potential: 10V；Collision cell exit potential:
14V；The ion selector channel of test object: general reed Ka Bili, [M+H]+, m/z 368.4/196.0, DP 96V, CE 40eV；
The general reed Ka Bili-of Isotopic Internal Standard13CD3, [M+H]+, m/z 374.4/198.0, DP 91V, CE 43eV；
(4) it calculates: internal standard method is used, with general reed Ka Bili and the general reed Ka Bili-of Isotopic Internal Standard13CD3Peak area ratio generation
Enter calibration curve equation and calculates general reed Ka Bili concentration.
2. the method for general reed Ka Bili concentration in measurement blood plasma according to claim 1, which is characterized in that in step (1),
Accurate in 10mL teat glass that plasma sample 0.4mL is added, 10ngmL is added in precision-1The general reed Ka Bili of Isotopic Internal Standard
-13CD31molL is added in 100 μ L of solution-1Sodium hydroxide 80 μ L, ethyl acetate 4mL, vortex vibrates 10min, 2000r
min-1It is centrifuged 10min, draws upper organic phase 3mL, centrifugal concentrating volatilizes at 40 DEG C, and 80% (v/v) methanol aqueous solution 200 is added
μ L redissolves, and vortex 1min, 12000g are centrifuged 5min, and 150 μ L of Aspirate supernatant is analyzed.
3. the method for general reed Ka Bili concentration in measurement blood plasma according to claim 1, which is characterized in that the blood plasma
To take orally the blood plasma after the general reed Ka Bili of succinic acid.
4. the method for general reed Ka Bili concentration in measurement blood plasma according to claim 1, which is characterized in that the blood plasma is
The blood plasma of human or animal.
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