CN106970163B - aceglutamide metabolite identification and detection method - Google Patents
aceglutamide metabolite identification and detection method Download PDFInfo
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- CN106970163B CN106970163B CN201710190978.2A CN201710190978A CN106970163B CN 106970163 B CN106970163 B CN 106970163B CN 201710190978 A CN201710190978 A CN 201710190978A CN 106970163 B CN106970163 B CN 106970163B
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Abstract
The invention discloses an identification and detection method of an aceglutamide metabolite, which comprises the following steps: (1) taking a gulf-red injection liquid tail vein injection SD rat, sampling blood at a time point for 5 min-8 h, and centrifugally separating blood plasma; (2) adding acetonitrile into plasma, wherein the volume ratio of the plasma to the acetonitrile is 1: 3-3.5, uniformly mixing, centrifuging, and taking the supernatant as a sample to be detected; (3) the determination method comprises the following steps: the method is characterized in that a quadrupole rod-linear ion trap type tandem mass spectrometer is adopted to carry out gradient elution separation on a sample, MIM-IDA and Q3MI-IDA scanning methods are combined, and a method for identifying and detecting the acetyl glutamine metabolites in one injection sample is simultaneously completed through LightSight software. It was found that 3 possible metabolites of acetylglutamine (acetylglutamate, glutamine, glutamate) in vivo were detected by the MIM-IDA-EPI collection pattern. 3 isomer peaks with different retention times can be found in both the aceglutamide standard and the plasma sample, and the secondary spectra are consistent. Gamma aminobutyric acid was not found, presumably because it is more present in the nervous system due to the different tissue distribution. The method is high in sensitivity, reliable and rapid, and the establishment of the method provides a foundation for qualitative and quantitative analysis of similar medicines in the future.
Description
Technical Field
the invention belongs to the field of drug detection and analysis, and particularly relates to an aceglutamide metabolite identification and detection method.
background
the aceglutamide has effects of maintaining nerve stress ability, improving brain function, etc. The acetylglutamide is first decomposed into gamma-aminobutyric acid (GABA) and glutamic acid in astrocytes after passing through the blood brain barrier. GABA is transported and released from glial cells and then binds to GABA receptors of neurons, so that postsynaptic neuron excitation is inhibited, release of Excitatory Amino Acid (EAA) is inhibited, excitotoxicity is resisted, and nerves are protected; GABA can improve the activity of glucose phosphate esterifying enzyme and promote the metabolism of glucose; GABA can also promote acetylcholine synthesis, improve nerve cell metabolism, maintain nerve stress capability, and improve brain function. The aceglutamide has the function of reducing blood ammonia, and glutamic acid in astrocytes is converted into glutathione, so that the glutathione becomes an important antioxidant and has an important neuroprotective effect in cerebral ischemia and nervous system degenerative diseases;
the flos Carthami injection (national Standard H22026638) is a compound preparation, contains aceglutamide and flos Carthami extract as effective components, and has anticoagulant, antithrombotic, vasodilating, microcirculation improving, and oxygen free radical resisting effects. Therefore, the pharmacodynamic material basis of the aceglutamide is evaluated by a scientific and accurate method, and the understanding of the metabolite and the pathway of the aceglutamide has important significance for the clinical application of the oryzanol injection and the aceglutamide;
the liquid chromatography-mass spectrometry (LC-MS) technology can carry out on-line analysis and detection on related components, provides rich compound structure information, has important significance for conjecturing the structure of unknown metabolites due to strong selectivity and good fragment ion reproducibility, and is faster and more sensitive than the existing chemical structure analysis means. Quadrupole-linear ion trap type tandem mass spectrometers have the distinct feature that they retain all the functions of triple quadrupole types, such as daughter ion scanning (PROS), parent ion scanning (PRES), Neutral Loss Scanning (NLS) and multiple or selective reaction monitoring (MRM or SRM); and the multi-stage ion scanning function of the ion trap is increased, and the sensitivity of the full scanning mode is improved. In addition, functions of enhanced full scan (EMS), enhanced electron ion scan (EPI), enhanced resolution Q3 scan (ERMS), time delay fragmentation scan (TDF) and multi-charge enhanced scan are added; and automatic switching scanning (IDA) and other software functions. Meanwhile, the defects of the traditional 3D ion trap, such as low mass cut-off phenomenon (1/3 effect), low collision efficiency, poor quantitative analysis performance and the like, are overcome. Therefore, the QTRAP type is a tandem mass spectrometer integrating multiple specific qualitative functions and quantitative analysis functions, and can be widely applied to multiple fields of drug analysis, qualitative and quantitative analysis of drug metabolites, new drug development and research and the like.
Disclosure of Invention
the invention aims to provide an identification and detection method for aceglutamide metabolites, which specifically adopts a quadrupole-linear ion trap type tandem mass spectrometer and combines MIM-IDA and Q3MI-IDA scanning methods to simultaneously complete the identification and detection method for the aceglutamide metabolites in one injection;
The technical scheme adopted by the invention is as follows:
an aceglutamide metabolite identification and detection method, comprising the steps of:
(1) the oryza sativa injection is injected into SD rats in tail vein, and the injection amount is 8-15 mg/kg. Sampling blood at a time point of 5 min-8 h, placing the blood sample in a heparinized centrifugal tube, and centrifugally separating plasma;
(2) the blood sample processing method comprises the following steps: and (3) sucking the plasma by a microsyringe, adding acetonitrile, wherein the volume ratio of the plasma to the acetonitrile is 1: 3-3.5, mixing the mixture by vortex, centrifuging the mixture, and taking the supernatant as a sample to be detected;
(3) Detecting and analyzing a sample by adopting high performance liquid chromatography-triple quadrupole linear ion trap tandem mass spectrometry, wherein the instrument conditions are as follows:
a. chromatographic conditions are as follows: shimadzu 20 ADXR;
The column temperature is 40-60 ℃;
the flow rate is 0.5-1.0 mL/min;
the mobile phase A is water (5 mM ammonium acetate, pH 4.0-6.2);
The mobile phase B is acetonitrile;
chromatographic column and elution mode: BEH amide column, gradient elution: 5% -60% of a water phase;
b. mass spectrum conditions AB SCIEX Qtrap 4500;
Scan Mode: ESI Negative Mode;
air curtain air CUR 25 psi;
the spraying voltage IS IS 5500V;
the ion source temperature TEM is 500-650 ℃;
60 psi of atomizing gas GS 1;
60 psi of heated gas GS 2;
collision gas CAD, Medium;
(4) according to the metabolism characteristics of the aceglutamide, mass spectrum is detected by adopting MIM-IDA and Q3MI-IDA methods, Multiple Ion Monitoring (MIM) is used as a pre-scanning mode, and the working flow of MIM-IDA-EPI is adopted. The QTRAP system carries out metabolite identification by combining with LightSight software;
further, in the step (1), the oryza sativa injection is injected into SD rats in tail vein, and the injection amount is 10 mg/kg, 5min, 15min, 30min, 45min, 1h, 1.5h, 2h, 4h, 6h and 8 h. Sampling blood by vein at different time points, placing the blood sample in a heparinized centrifugal tube, and centrifugally separating plasma at 5000 r/min;
in the step (2), the blood sample processing method comprises the following steps: the microsampler absorbs 200 mu L of plasma, acetonitrile is added, and the volume ratio of the plasma to the acetonitrile is 1: 3.5, mixing uniformly by vortex for 30s, centrifuging at 12000r for 10min, and taking the supernatant as a sample to be detected;
in the step (3), the column temperature is 40 ℃, and the flow rate is 0.5 mL/min;
in the step (3), the mobile phase A is water (5 mM ammonium acetate, pH 6.2);
The step (3) is operated according to the following method: gradient elution conditions: 0-1 min, wherein the volume fraction of the mobile phase A is 5%; increasing the volume fraction of the mobile phase A from 5% to 10% in 1-5 min; 5-10 min, increasing the volume fraction of the mobile phase A from 10% to 60%; 10-12 min, the volume fraction of the mobile phase A is 60%, 12-12.1 min, the volume fraction of the mobile phase A is reduced from 60% to 5%, and after 12.1min, the volume fraction of the mobile phase A is kept at 5%. In gradient elution, the sum of the volume fractions of mobile phase a and mobile phase B is 100%;
in the step (3), the ion source temperature TEM is 575 ℃;
more particularly, the process of the invention is preferably operated as follows:
(1) injecting the gulfweed injection into SD rat via tail vein, collecting blood at time points of 5min, 15min, 30min, 45min, 1h, 1.5h, 2h, 4h, 6h and 8h, placing the blood sample in heparinization centrifuge tube, and centrifuging at 5000 r/min to separate plasma;
(2) The blood sample processing method comprises the following steps: the microsampler absorbs 200 mu L of plasma, acetonitrile is added, and the volume ratio of the plasma to the acetonitrile is 1: 3.5, mixing uniformly by vortex for 30s, centrifuging at 12000r for 10min, and taking the supernatant as a sample to be detected;
(3) the sample is detected and analyzed by adopting a quadrupole-linear ion trap type tandem mass spectrometer and combining MIM-IDA and Q3MI-IDA scanning methods, and the instrument conditions are as follows:
a. chromatographic conditions are as follows: shimadzu 20 ADXR;
the column temperature is 40 ℃;
the flow rate is 0.5 mL/min;
Mobile phase a water (5 mM ammonium acetate, pH 6.2);
the mobile phase B is acetonitrile;
Chromatographic column and elution mode: BEH amide column, gradient elution: 0-1 min, wherein the volume fraction of the mobile phase A is 5%; increasing the volume fraction of the mobile phase A from 5% to 10% in 1-5 min; 5-10 min, increasing the volume fraction of the mobile phase A from 10% to 60%; 10-12 min, the volume fraction of the mobile phase A is 60%, 12-12.1 min, the volume fraction of the mobile phase A is reduced from 60% to 5%, and after 12.1min, the volume fraction of the mobile phase A is kept at 5%. In gradient elution, the sum of the volume fractions of mobile phase a and mobile phase B is 100%;
b. mass spectrum conditions AB SCIEX Qtrap 4500;
scan Mode: ESI Negative Mode;
Air curtain air CUR 25 psi;
The spraying voltage IS IS 5500V;
The ion source temperature TEM is 575 ℃;
60 psi of atomizing gas GS 1;
60 psi of heated gas GS 2;
collision gas CAD, Medium;
(4) According to the metabolism characteristics of the aceglutamide, mass spectrometry is detected by using MIM-IDA and Q3MI-IDA methods, Multiple Ion Monitoring (MIM) is used as a pre-scanning mode, and the working flow of MIM-IDA-EPI is used, wherein the mode adopts an MRM method that Q3 and Q1 are set to be the same in mass-to-charge ratio, 101 pairs of ions are detected in an experiment, the mass range is 100.1Da-200.1 Da, a possible biotransformation process is not required to be predicted in the mode, CE is set to be 5V in order to avoid fragmentation of parent ions in a Q2 collision cell, the residence time and the pause time of each pair of ions are set to be 1 millisecond, and one scanning period needs 0.8 seconds, and a RAP ® system is combined with LightSight ® software to identify metabolites;
the detection method finds that 3 possible metabolites (acetylglutamic acid, glutamine, glutamic acid) of acetylglutamine in the body are detected through the MIM-IDA-EPI collection mode. 3 isomer peaks with different retention times can be found in both the aceglutamide standard and the plasma sample, and the secondary spectra are consistent. Except for acetylglutamine, acetylglutamic acid, glutamine and glutamic acid are all endogenous substances. Therefore, the time course is different from that of the general exogenous drug metabolites. No gamma-aminobutyric acid was found in the experiment. Presumably, gamma aminobutyric acid is more present in the nervous system, probably because of the different tissue distribution. The method is high in sensitivity, reliable and rapid, and the establishment of the method provides a basis for qualitative and quantitative analysis of similar medicines in the future;
the embodiments of the present invention will be described in further detail with reference to the drawings and examples.
drawings
FIG. 1: secondary spectrum of aceglutamide under negative ion mode;
FIG. 2: a map of possible metabolic pathways for acetylglutamide;
FIG. 3: acetylglutamide mass spectrum and time profile in plasma;
FIG. 4: an acetylglutamate mass spectrum and time profile in plasma;
FIG. 5: glutamine mass spectrum and time profile in plasma;
FIG. 6: glutamic acid mass spectrum and time profile in plasma.
Detailed Description
In order to make the objects, technical solutions and positive effects of the present invention more apparent, the present invention is further described in detail by the following examples. The following description of specific embodiments is intended to be illustrative of the invention and not to be limiting;
aceglutamide metabolite identification and detection method
firstly, an instrument:
quadrupole-linear ion trap type tandem mass spectrometer (liquid phase Shimadzu 20ADXR, mass spectrum AB SCIEX Qtrap 4500);
secondly, sample preparation:
injecting the gulong red injection into SD rat via tail vein, collecting blood at time points of 5min, 15min, 30min, 45min, 1h, 1.5h, 2h, 4h, 6h and 8h, placing the blood sample in heparinization centrifuge tube, and centrifuging at 5000 r/min to separate plasma. The microsampler absorbs 200 mu L of plasma, acetonitrile is added, and the volume ratio of the plasma to the acetonitrile is 1: 3.5, mixing uniformly by vortex for 30s, centrifuging at 12000r for 10min, and taking the supernatant as a sample to be detected;
thirdly, detection conditions are as follows:
the sample is detected and analyzed by adopting a quadrupole-linear ion trap type tandem mass spectrometer and combining MIM-IDA and Q3MI-IDA scanning methods, and the instrument conditions are as follows:
a. chromatographic conditions are as follows: shimadzu 20 ADXR;
the column temperature is 40 ℃;
flow rate of 0.5 mL/min
mobile phase a water (5 mM ammonium acetate, pH 6.2);
The mobile phase B is acetonitrile;
Chromatographic column and elution mode: BEH amide column, gradient elution: 0-1 min, wherein the volume fraction of the mobile phase A is 5%; increasing the volume fraction of the mobile phase A from 5% to 10% in 1-5 min; 5-10 min, increasing the volume fraction of the mobile phase A from 10% to 60%; 10-12 min, the volume fraction of the mobile phase A is 60%, 12-12.1 min, the volume fraction of the mobile phase A is reduced from 60% to 5%, and after 12.1min, the volume fraction of the mobile phase A is kept at 5%. In gradient elution, the sum of the volume fractions of mobile phase a and mobile phase B is 100%;
b. mass spectrum conditions AB SCIEX Qtrap 4500;
Scan Mode: ESI Negative Mode;
Air curtain air CUR 25 psi;
The spraying voltage IS IS 5500V;
the ion source temperature TEM is 575 ℃;
60 psi of atomizing gas GS 1;
60 psi of heated gas GS 2;
collision gas CAD, Medium;
fourth, analysis method
according to the metabolism characteristics of the aceglutamide, mass spectrometry is detected by using MIM-IDA and Q3MI-IDA methods, Multiple Ion Monitoring (MIM) is used as a pre-scanning mode, and the working flow of MIM-IDA-EPI is used, wherein the mode adopts an MRM method that Q3 and Q1 are set to be the same in mass-to-charge ratio, 101 pairs of ions are detected in an experiment, the mass range is 100.1Da-200.1 Da, a possible biotransformation process is not required to be predicted in the mode, CE is set to be 5V in order to avoid fragmentation of parent ions in a Q2 collision cell, the residence time and the pause time of each pair of ions are set to be 1 millisecond, and one scanning period needs 0.8 seconds, and a RAP ® system is combined with LightSight ® software to identify metabolites;
The identification of acetylglutamide metabolites is summarized:
detecting 3 possible metabolites (acetylglutamic acid, glutamine and glutamic acid) of acetylglutamine in vivo by an MIM-IDA-EPI collection mode;
(② 3 isomer peaks with different retention time can be found in the standard product of aceglutamide and the plasma sample, and the secondary spectrogram is consistent;
③ apart from aceglutamide, acetylglutamic acid, glutamine and glutamic acid are all endogenous substances. Therefore, the time curve is different from the time curve of the general exogenous drug metabolites;
and gamma-aminobutyric acid is not found in the experiment. Presumably, gamma aminobutyric acid is more present in the nervous system due to the different tissue distribution;
the method is high in sensitivity, reliable and rapid, and the establishment of the method provides a basis for qualitative and quantitative analysis of similar medicines in the future; details not described in the present specification belong to the prior art known to those skilled in the art.
Claims (4)
1. an aceglutamide metabolite identification and detection method, characterized in that said method comprises the following steps: (1) injecting the oryza sativa injection into SD rats in tail vein, wherein the injection amount is 8-15 mg/kg; sampling blood at a time point of 5 min-8 h, placing the blood sample in a heparinized centrifugal tube, and centrifugally separating plasma;
(2) the blood sample processing method comprises the following steps: and (3) sucking the plasma by a microsyringe, adding acetonitrile, wherein the volume ratio of the plasma to the acetonitrile is 1: 3-3.5, mixing the mixture by vortex, centrifuging the mixture, and taking the supernatant as a sample to be detected;
(3) detecting and analyzing a sample by adopting high performance liquid chromatography-triple quadrupole linear ion trap tandem mass spectrometry, wherein the instrument conditions are as follows:
a. chromatographic conditions are as follows: shimadzu 20 ADXR;
Column temperature: c, 40-60 ℃;
flow rate: 0.5-1.0 mL/min;
mobile phase A: water, 5mM ammonium acetate, pH 6.2;
mobile phase B: acetonitrile;
chromatographic column and elution mode: BEH amide column, gradient elution: 5% -60% of a water phase;
b. mass spectrum conditions: AB SCIEX Qtrap 4500;
scan Mode: ESI Negative Mode;
air curtain air CUR: 25 psi;
spray voltage IS: 5500V;
ion source temperature TEM: 500-650 ℃;
atomizing gas GS1: 60 psi;
heating gas GS2: 60 psi;
collision gas CAD: medium;
the method comprises the following steps: gradient elution conditions: 0-1 min, wherein the volume fraction of the mobile phase A is 5%; increasing the volume fraction of the mobile phase A from 5% to 10% in 1-5 min; 5-10 min, increasing the volume fraction of the mobile phase A from 10% to 60%; 10-12 min, wherein the volume fraction of the mobile phase A is 60%, 12-12.1 min, the volume fraction of the mobile phase A is reduced from 60% to 5%, and after 12.1min, the volume fraction of the mobile phase A is kept at 5%; in gradient elution, the sum of the volume fractions of mobile phase a and mobile phase B is 100%;
(4) According to the metabolism characteristics of the aceglutamide, mass spectrum is detected by adopting MIM-IDA and Q3MI-IDA methods, Multiple Ion Monitoring (MIM) is used as a pre-scanning mode, and the MIM-IDA-EPI working flow is adopted; in this mode, 101 pairs of ions were detected in the experiment using the MRM method with Q3 and Q1 set to the same mass-to-charge ratio; the mass range is 100.1Da-200.1 Da, and the possible biotransformation process does not need to be predicted in the mode; to avoid fragmentation of the parent ions in the Q2 collision cell, CE was set to 5V; the dwell and dwell time for each pair of ion pairs was set to 1 millisecond, with one scan cycle taking 0.8 seconds; the QTRAP system carries out metabolite identification by combining with LightSight software.
2. The method of claim 1, wherein in the step (1), the oryza sativa injection is injected into SD rats through tail vein injection, the injection amount is 10 mg/kg, 5min, 15min, 30min, 45min, 1h, 1.5h, 2h, 4h, 6h and 8h, the blood is collected through vein by time points, the blood sample is placed in a heparinized centrifuge tube, and plasma is centrifugally separated at 5000 r/min.
3. The method according to claim 1, wherein in the step (2), the blood sample processing method comprises: the microsampler absorbs 200 mu L of plasma, acetonitrile is added, and the volume ratio of the plasma to the acetonitrile is 1: 3.5, mixing evenly by vortex for 30s, centrifuging for 10min at 12000r, and taking the supernatant as a sample to be detected.
4. the method according to claim 1, wherein in step (3), the ion source temperature TEM: 575 ℃.
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| CN1965878A (en) * | 2005-11-18 | 2007-05-23 | 北京天新园医药科技开发有限公司 | Pharmaceutical composition containing aceglutamide and safflower effective ingredients and formulation thereof |
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| CN1965878A (en) * | 2005-11-18 | 2007-05-23 | 北京天新园医药科技开发有限公司 | Pharmaceutical composition containing aceglutamide and safflower effective ingredients and formulation thereof |
| CN101120959A (en) * | 2006-08-08 | 2008-02-13 | 阿尔贝拉医药(中国)有限公司 | Application of guhong injection for treating lung cancer |
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