CN101105479A - Method for determining human plasma phenytoin and its precursor drug and metabolite - Google Patents
Method for determining human plasma phenytoin and its precursor drug and metabolite Download PDFInfo
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- CN101105479A CN101105479A CNA2007100447994A CN200710044799A CN101105479A CN 101105479 A CN101105479 A CN 101105479A CN A2007100447994 A CNA2007100447994 A CN A2007100447994A CN 200710044799 A CN200710044799 A CN 200710044799A CN 101105479 A CN101105479 A CN 101105479A
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Abstract
The invention belongs to the medical inspection field, relates to an analysis detection method of drug in the body of a person, and specifically relates to the method that the densities of fosphenytoin, phenytoin and 4'-hydroxyl phenytoin which is the main metabolite of fosphenytoin and phenytoin in can be detected at the same time. The method in the invention is characterized in that pilot sample is pretreated; fosphenytoin, phenytoin and 4'-hydroxyl phenytoin are separated with each other in an acidity flowing phase chromatographic column and are detected by UV detector. The method in the invention has the advantages of little sample, easy, swift and sensitive operation and short analysis period; furthermore, the method in the invention doesn't need expensive equipment and reagent, is suitable for clinical conventional detection and can be used to adjust the drug dose, which can guarantee safe and effective prescription and has the important clinical practice significance.
Description
Technical field
The invention belongs to field of medical examination, relate to the analysis determining method of drug disposition, be specifically related to a kind of measure Fosphenytoin in the human plasma, phenytoinum naticum and metabolic product 4 thereof '-method of hydroxyl phenytoinum naticum.
Background technology
(phenytoin PHT) is the efficient medicine of acute epileptic attack of treatment or status epilepticus to phenytoinum naticum.Because of its poorly water-soluble and alkaline strong, its use value is affected.Recently (antiepileptic drugs, AEDs) (fosphenytoin FOS) is the phosphate prodrug of PHT to Fosphenytoin to the antiepileptic of Yan Jiukaifa parenteral administration.Because its high polarity and suitable pH can be by drip-feed or administered intramuscular.FOS itself does not have tangible pharmacologically active, and administration is after the phosphate metabolism in blood and the tissue is to bring into play antiepileptic action behind the phenytoinum naticum.Phenytoinum naticum mainly by 4 '-hydroxylation metabolism becomes 4 '-the hydroxyl phenytoinum naticum (4 '-hydroxyphenytoin, 4 '-HPPH), and then generate glucuronide and excrete.FOS has interference to determination of immunological methods PHT, often makes the PHT measured value be higher than actual concentrations.Do not see as yet at present both at home and abroad about measure simultaneously FOS in the human plasma, PHT and 4 '-relevant report of the concentration of HPPH.Therefore research and development efficient, sensitive, detect the method for said medicine concentration in the blood plasma accurately, in order to adjust dosage, guarantee drug safety, effectively have an important practice significance of facing.
Summary of the invention
The objective of the invention is to overcome the defective of prior art, provide a kind of easy, quick, sensitive, can measure Fosphenytoin (fosphenytoin in the body simultaneously, FOS), phenytoinum naticum (phenytoin, PHT) and 4 '-the hydroxyl phenytoinum naticum (4 '-hydroxyphenytoin, 4 '-HPPH) method of blood concentration.
This method need not expensive equipment and reagent, has easy and simple to handle, quick, few, the low cost and other advantages of blood plasma consumption, is fit to conventional therapeutic drug monitoring.
The technical scheme of this method is: after the testing sample pre-service, separate in chromatographic column through acid moving phase, detect with UV-detector.
Comprise the steps:
1) sample pretreatment
Get testing sample, after the phosphoric acid acidifying, add quantitative organic solvent extract, centrifugal after, get that upper strata organic layer solution nitrogen dries up, moving phase redissolves, and gets the supernatant sample introduction;
Described phosphoric acid souring soln is 20～-40% phosphoric acid solutions, and described organic solvent is an ethyl acetate solution;
2) sample separation
Adopt universal liquid-phase chromatographic column, its filler is Agilent RX-C
8, the high performance liquid chromatogram system adopts universal UV-detector and high-pressure pump, and moving phase is acid, isocratic elution;
Described moving phase adopts the mixed liquor of 0.08～0.1% trifluoroacetic acid (TFA) aqueous solution (pH=2.1～2.5), acetonitrile and methyl alcohol;
Described isocratic elution pattern optimum selection 0.08～0.1%TFA aqueous solution: acetonitrile: methyl alcohol is 60: 17: 23, V/V/V;
3) sample detection
Adopt universal UV-detector detect FOS, PHT and 4 '-peak area of HPPH, the ultraviolet detection wavelength is 210 ± 1nm, is converted into concentration with the typical curve equation.
This method has the following advantages:
1. sampling quantity is few: measure a duplicate samples and only need the 0.1ml plasma sample;
2. pre-service is easy: a step ethyl acetate extraction, and simple and easy to do, be applicable to conventional sense;
3. selectivity is strong: endogenous material, antiepileptic commonly used and OTC (over-the-counter) are not disturbed measuring;
4. minute is short: it only is 12min that process is measured in whole stratographic analysis.
Described FOS, PHT and 4 '-HPPH setting-out line scope is respectively 1～400,0.5～50 and 0.5～10mgL
-1, the method recovery is all 100 ± 12%, in a few days and precision in the daytime (relative standard deviation is RSD) all less than 11%.
The inventive method quick and precisely, easy and simple to handle, cost is low, is fit to routine clinical monitoring, in order to adjust dosage, guarantees drug safety and effectively to have the important practice significance of facing.
Description of drawings
Fig. 1: blank plasma chromatogram
Fig. 2: the chromatogram of intravenous injection Fosphenytoin 18mg/kg experimenter 0.5h,
Wherein, (concentration is 2.87mgL to 1:4 '-hydroxyl phenytoinum naticum
-1); 2: (concentration is 44.8mgL to Fosphenytoin
-1); 3: interior mark (Propranolol Hydrochloride); 4: (concentration is 16.2mgL to phenytoinum naticum
-1).
Fig. 3: the chromatogram of intravenous injection Fosphenytoin 16mg/kg experimenter 0.5h,
Wherein, (concentration is 3.23mgL to 1:4 '-hydroxyl phenytoinum naticum
-1); 2: (concentration is 39.8mgL to Fosphenytoin
-1); 3: interior mark (Propranolol Hydrochloride); 4: (concentration is 18.7mgL to phenytoinum naticum
-1).
Embodiment
Embodiment 1:
Chromatographic condition
HPLC system: chromatographic column Agilent RX-C
8(250mm * 4.6mm, 5 μ m), and moving phase employing 0.08%TFA aqueous solution-acetonitrile-methyl alcohol (60: 17: 23, V/V/V), flow velocity: 1.5mLmin
-1Column temperature: 40 ℃; Ultraviolet detection wavelength: 210 ± 1nm.
The plasma sample pre-service
The accurate plasma sample 100 μ L that draw put in the 1.5mL centrifuge tube, add 50 μ L, 20% phosphoric acid acidifying, and vortex 0.5min adds 1mL and contains 10mgL
-1The ethyl acetate solution extraction of Propranolol Hydrochloride, vortex 5min, centrifugal (15,000 * g, 4 ℃) 10min, get upper strata extract 800 μ L, transfer in the 5mL centrifuge tube, place 40 ℃ of water-baths, nitrogen dries up, add moving phase 100 μ L, get supernatant 20 μ L sample introduction analyses, internal standard method is with peak area quantification.
Specificity
Get 10 of separate sources do not take Fosphenytoin, phenytoinum naticum and 4 '-experimenter's of hydroxyl phenytoinum naticum blank plasma, measure according to above-mentioned sample pretreatment and assay method, do not find that the blood plasma endogenous material has interference to the said determination component, (see figure 1).In addition, common drug combination valproic acid, phenobarbital, carbamazepine, doxepin, intrazepam, stable, clonazepam, haloperole, metronidazole, paracetamol, nifedipine, brufen, Acyclovir etc. are not disturbed measuring.In mark Propranolol, Fosphenytoin, phenytoinum naticum and 4 '-the typical chromatographic retention of hydroxyl phenytoinum naticum is respectively 9.1,5.4,10.7 and 4.6min, peak shape is good, separates fully.Whole stratographic analysis process time is 12min.
Linear test
Precision take by weighing FOS, PHT and 4 '-the HPPH standard substance is an amount of, uses 50% dissolve with methanol, is diluted to serial working fluid, adds an amount of blank human plasma again, is mixed with to contain FOS 1,10 100,200,300,400mgL
-1, PHT 0.5,2.5,12.5,25,37.5,50mgL
-1With 4 '-HPPH 0.5,1.25,2.5,5.0,7.5,10.0mgL
-1The standard blood sample.Get blood plasma 100 μ L, by the operation of " plasma sample pre-service " method.Internal standard method is done weighting (1/C) linear regression with component to be measured and interior target peak area ratio (A) and concentration of component to be measured (C), FOS, PHT and 4 '-the HPPH range of linearity is respectively 1～400,0.5～50 and 0.5～10mgL
-1, FOS, PHT and 4 '-HPPT minimum quantitatively be limited to 1.0,0.5 and 0.5mgL
-1, three's typical curve regression equation is respectively: FOS A=0.02241 C-0.01326, r=0.9991; PHTA=0.03397C-0.002 98, r=0.9994; HPPT A=0.04400 C+0.00083, r=0.9992.
Accuracy and precision
Precision take by weighing FOS, PHT and 4 '-the HPPH standard substance is an amount of, 50% dissolve with methanol also is diluted to serial working fluid, adds an amount of blank human plasma again, is mixed with to contain FOS 2.5,180,360mgL
-1, PHT 1,20,40mgL
-1With 4 '-HPPT 1.0,4.0,8.0mgL
-1Serial blood sample, respectively get blood plasma 100 μ L, by " plasma sample pre-service " method operation, investigate in a few days and precision in the daytime and accuracy.Calculate its measured concentration according to equation of linear regression, calculate actual measurement mean value, deviation and the relative standard deviation (RSD) of every kind of concentration, wherein (C
Actual measurement-C
Theoretical)/C
Theoretical* 100% is deviation, and standard deviation/mean value * 100% is the relative standard deviation.The result shows, three kinds of determinands in a few days with day to day precision all less than 11.6%, deviation is less than 10.8%.
Table 1 shown FOS, PHT and 4 '-HPPH in a few days, day to day precision and accuracy.
The experimenter that this method is used for the intravenous injection Fosphenytoin detects, measure simultaneously Fosphenytoin, phenytoinum naticum and metabolic product 4 thereof '-concentration of hydroxyl phenytoinum naticum, Fig. 2 is certain experimenter's an analysis chromatogram, three's concentration is respectively 44.8,16.2 and 2.87mgL
-1
Embodiment 2:
Chromatographic condition
HPLC system: chromatographic column Agilent RX-C
8(250mm * 4.6mm, 5 μ m), and moving phase employing 0.1%TFA aqueous solution-acetonitrile-methyl alcohol (60: 17: 23, V/V), flow velocity: 1.5mLmin
-1Column temperature: 40 ℃; Ultraviolet detection wavelength: 210 ± 1nm; Sample size: 20 μ L.
The plasma sample pre-service
The accurate plasma sample 100 μ L that draw put in the 5mL centrifuge tube, add 25 μ L40% phosphoric acid acidifyings, and vortex 0.5min adds 2mL and contains 10mgL
-1The ethyl acetate solution extraction of Propranolol Hydrochloride, vortex 5min, centrifugal (15,000 * g, 4 ℃) 10min, get upper strata extract 1.8mL, transfer in the 5mL centrifuge tube, place 40 ℃ of water-baths, nitrogen dries up, add moving phase 100 μ L DLs and redissolve, get supernatant 20 μ L sample introduction analyses, internal standard method is with peak area quantification.
Specificity
Get 10 of separate sources do not take Fosphenytoin, phenytoinum naticum and 4 '-experimenter's of hydroxyl phenytoinum naticum blank plasma, measure according to above-mentioned sample pretreatment and assay method, do not find that the blood plasma endogenous material has interference to the said determination component.In addition, common drug combination and non-prescribed medicine (with listed medicine among the embodiment 1) are not disturbed measuring.In mark Propranolol, Fosphenytoin, phenytoinum naticum and 4 '-the typical chromatographic retention of hydroxyl phenytoinum naticum is respectively 9.1,5.4,10.8 and 4.6min, peak shape is good, separates fully.Whole stratographic analysis process time is 12min.
Linear test
Precision take by weighing FOS, PHT and 4 '-the HPPH standard substance is an amount of, uses 50% dissolve with methanol, is diluted to serial working fluid, adds an amount of blank human plasma again, be mixed with to contain FOS 1,10,100,200,300,400mgL
-1, PHT 0.5,2.5,12.5,25,37.5,50mgL
-1With 4 '-HPPH 0.5,1.25,2.5,5.0,7.5,10.0mgL
-1The standard blood sample.Get blood plasma 100 μ L, by the operation of " plasma sample pre-service " method.Internal standard method is done weighting (1/C) linear regression with component to be measured and interior target peak area ratio (A) and concentration of component to be measured (C), FOS, PHT and 4 '-the HPPH range of linearity is respectively 1～400,0.5～50 and 0.5～10mgL
-1, FOS, PHT and 4 '-HPPT minimum quantitatively be limited to 1.0,0.5 and 0.5mgL
-1, three's typical curve regression equation is respectively: FOS A=0.01926 C-0.01427, r=0.9993; PHTA=0.04523C-0.00135, r=0.9995; HPPTA=0.03568 C+0.00079, r=0.9995.
Accuracy and precision
Precision take by weighing FOS, PHT and 4 '-the HPPH standard substance is an amount of, 50% dissolve with methanol also is diluted to serial working fluid, adds an amount of blank human plasma again, is mixed with to contain FOS 2.5,180,360mgL
-1, PHT 1,20,40mgL
-1With 4 '-HPPT 1,4.0,8.0mgL
-1Serial blood sample, respectively get blood plasma 100 μ L, by " plasma sample pre-service " method operation, investigate in a few days and precision in the daytime and accuracy.Calculate its measured concentration according to equation of linear regression, calculate actual measurement mean value, deviation and the relative standard deviation (RSD) of every kind of concentration, wherein (C
Actual measurement-C
Theoretical)/C
Theoretical* 100% is deviation, and standard deviation/mean value * 100% is the relative standard deviation.The result shows, three kinds of determinands in a few days with day to day precision all less than 8%, relative deviation is less than 9%.
Table 2 shown FOS, PHT and 4 '-HPPH in a few days, day to day precision and accuracy.
This method is used for the experimenter of intravenous injection Fosphenytoin, measure simultaneously Fosphenytoin, phenytoinum naticum and metabolic product 4 thereof '-concentration of hydroxyl phenytoinum naticum, Fig. 3 is certain experimenter's an analysis chromatogram, three's concentration is respectively 39.8,18.7 and 3.23mgL
-1
Table 1
| Theoretical concentration (mgL -1) | Measure concentration (mgL -1) (mean+SD) | Precision RSD (%) | Accuracy Bias (%) | |
| Fosphenytoin | (n=6) 1 2.5 18 360 between (n=6) 1 2.5 180 360 days in a few days | 0.892±-0.0512 2.32±0.0829 194±3.81 373±14.4 0.993±0.0698 2.424±0.0570 186±8.56 356±18.6 | 5.74 3.57 1.97 3.86 7.03 2.36 4.61 5.22 | -10.8 -7.20 1.11 3.61 -0.70 -3.20 3.33 -1.11 |
| Phenytoinum naticum | (n=6) 0.5 1 20 40 between (n=6) 0.5 1 20 40 days in a few days | 0.502±0.0456 1.02±0.0628 21.6±0.356 41.7±1.31 0.503±0.0586 0.991±0.771 21.3±0.691 42.1±1.02 | 9.08 6.16 1.65 3.14 11.6 7.78 3.25 2.42 | 0.40 2.00 8.00 4.25 0.60 -0.90 6.50 5.25 |
| 4 '-the hydroxyl phenytoinum naticum | (n=6) 0.5 148 between (n=6) 0.5 148 days in a few days | 0.468±0.0489 1.01±0.0621 4.06±0.0656 8.19±0.400 0.512±0.0538 0.999±0.0491 4.10±0.0117 8.24±0.271 | 10.4 6.15 1.62 4.88 10.5 4.91 2.86 3.29 | -6.40 1.84 1.52 2.38 2.41 -0.11 2.50 3.00 |
Table 2
| Theoretical concentration (mgL -1) | Measure concentration (mgL -1) (mean value scholar standard deviation) | Precision RSD (%) | Accuracy Bias (%) | |
| Fosphenytoin-- | (n=6) 1 2.5 180 360 between (n=6) 1 2.5 180 360 days in a few days | 0.914±0.0635 2.6l±0.0615 174±5.92 364±13.9 0.926±0.0664 2.68±0.0959 174±7.39 368±7.84 | 6.95 2.36 3.41 3.84 7.17 3.58 4.24 2.13 | -8.56 4.28 -3.62 1.25 -7.43 7.13 -3.19 2.31 |
| Phenytoinum naticum-- | (n=6) 0.5 1 20 40 between (n=6) 0.5 1 20 40 days in a few days | 0.472±0.0265 0.977±0.0225 19.5±0.499 38.6±1.27 0.469±0.0291 0.964±0.0371 20.5±0.7091 38.7±0.956 | 5.62 2.13 2.56 3.29 6.21 3.85 3.46 2.47 | -5.64 -2.26 -2.57 -3.41 -6.31 -3.64 2.48 -3.19 |
| 4 '-the hydroxyl phenytoinum naticum | (n=6) 0.5 148 between (n=6) 0.5 148 days in a few days | 0.536±0.0301 0.978±0.0210 4.15±0.1491 7.79±0.2671 0.542±0.0332 0.964±0.0227 4.16±0.1441 7.71±0.1914 | 5.61 2.15 3.59 3.43 6.14 2.35 3.46 2.48 | 7.15 -2.18 3.87 -2.66 8.46 -3.56 4.13 -3.54 |
Claims (3)
1. method of measuring phenytoinum naticum in the human plasma and pro-drug and metabolin, it is characterized in that the testing sample pre-service after, after chromatographic column is separated, detect with UV-detector, may further comprise the steps:
1) sample pretreatment
Get testing sample, after the phosphoric acid acidifying, add quantitative organic solvent extract, centrifugal after, get that upper strata organic layer solution nitrogen dries up, moving phase redissolves, and gets the supernatant sample introduction;
Described phosphoric acid souring soln is 20～-40% phosphoric acid solutions, and described organic solvent is an ethyl acetate solution;
2) sample separation
Adopt universal liquid-phase chromatographic column, its filler is Agilent RX-C
8, the high performance liquid chromatogram system adopts universal UV-detector and high-pressure pump, and moving phase is acid, isocratic elution;
Described moving phase adopts the mixed liquor of 0.08～0.1% trifluoroacetic acid (TFA) aqueous solution pH=2.1～2.5, acetonitrile and methyl alcohol;
Described isocratic elution pattern is 0.08～0.1%TFA aqueous solution: acetonitrile: methyl alcohol is 60: 17: 23, V/V/V;
3) sample detection
Adopt universal UV-detector to detect the peak area of phenytoinum naticum and pro-drug and metabolin, the ultraviolet detection wavelength is 210 ± 1nm, is converted into concentration with the typical curve equation.
2. the method for phenytoinum naticum and pro-drug and metabolin in the mensuration human plasma according to claim 1 is characterized in that its pro-drug of described phenytoinum naticum is a Fosphenytoin; Its metabolin of phenytoinum naticum is 4 '-the hydroxyl phenytoinum naticum.
3. the method for phenytoinum naticum and pro-drug and metabolin is characterized in that described step 2 in the mensuration human plasma according to claim 1) chromatographic condition in: chromatographic column adopting Agilent RX-C
8250mm * 4.6mm, 5 μ m; Flow velocity: 1.5mLmin
-1Column temperature: 40 ℃.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101419225B (en) * | 2008-11-06 | 2012-09-05 | 复旦大学附属华山医院 | Method for simultaneously determining mycophenolic acid ester, mycophenolic acid and metabolite thereof in human urine |
| CN104884029A (en) * | 2012-10-23 | 2015-09-02 | 赛拉诺斯股份有限公司 | Drug monitoring and regulation systems and methods |
| CN108037214A (en) * | 2017-12-28 | 2018-05-15 | 北京和合医学诊断技术股份有限公司 | Detect the liquid phase chromatography analytical method of dilantin sodium medicament contg in blood |
| CN110632235A (en) * | 2019-11-12 | 2019-12-31 | 北京和合医学诊断技术股份有限公司 | Method for detecting phenytoin sodium in blood |
| CN114646711A (en) * | 2020-12-21 | 2022-06-21 | 四川科瑞德制药股份有限公司 | Detection method of impurities related to hydroxymethyl phenytoin |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1971270B (en) * | 2005-11-24 | 2010-11-24 | 复旦大学附属华山医院 | Method for detecting blood concentration of multiple antiepileptic drugs simultaneously |
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2007
- 2007-08-10 CN CN200710044799A patent/CN100580448C/en not_active Expired - Fee Related
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101419225B (en) * | 2008-11-06 | 2012-09-05 | 复旦大学附属华山医院 | Method for simultaneously determining mycophenolic acid ester, mycophenolic acid and metabolite thereof in human urine |
| CN104884029A (en) * | 2012-10-23 | 2015-09-02 | 赛拉诺斯股份有限公司 | Drug monitoring and regulation systems and methods |
| CN108037214A (en) * | 2017-12-28 | 2018-05-15 | 北京和合医学诊断技术股份有限公司 | Detect the liquid phase chromatography analytical method of dilantin sodium medicament contg in blood |
| CN110632235A (en) * | 2019-11-12 | 2019-12-31 | 北京和合医学诊断技术股份有限公司 | Method for detecting phenytoin sodium in blood |
| CN114646711A (en) * | 2020-12-21 | 2022-06-21 | 四川科瑞德制药股份有限公司 | Detection method of impurities related to hydroxymethyl phenytoin |
| CN114646711B (en) * | 2020-12-21 | 2023-06-23 | 四川科瑞德制药股份有限公司 | Method for detecting hydroxymethyl phenytoin related impurities |
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