CN105588894A - Application of preclinical drug metabolism and pharmacokinetics key technology and research system to cefoxitin - Google Patents
Application of preclinical drug metabolism and pharmacokinetics key technology and research system to cefoxitin Download PDFInfo
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- CN105588894A CN105588894A CN201510924528.2A CN201510924528A CN105588894A CN 105588894 A CN105588894 A CN 105588894A CN 201510924528 A CN201510924528 A CN 201510924528A CN 105588894 A CN105588894 A CN 105588894A
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- 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
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Abstract
The invention provides an application of the preclinical drug metabolism and pharmacokinetics key technology and a research system to cefoxitin. The application includes the steps that 1, after cefoxitin in a certain concentration is fed to an experimental animal for a certain time, one or more biological samples are collected from blood, urine and feces; 2, the biological samples obtained in the step 1 are treated with the liquid-liquid extraction technology, the protein precipitation technology and the solid phase extraction technology, and corresponding solutions are prepared; 3, the solutions prepared in the step 2 are analyzed with liquid chromatogram-mass spectrum (LC-MS) and liquid chromatogram-tandem mass spectrum (LC-MS/MS). According to the application, the membrane permeation performance and the cell absorbing capacity of the cefoxitin can be further detected through Caco-2 cells, or detection of the in-vitro metabolism stability and identification of metabolite of the cefoxitin are achieved through the whole animal, S9, human intestine microsome and monoclonal purifying enzymes.
Description
Technical field
The present invention relates to the application at Cefoxitin of clinical prodrug dynamic metabolism key technology and research system.
Background technology
Cefoxitin to the anti-microbial property of gram-positive bacteria a little less than, strong to Gram-negative bacteria effect. Cefoxitin pairEscherichia coli, the white Salmonella of Cray, haemophilus influenzae, gonococcus, proteus mirabilis, the positive deformed rod of indolesBacterium etc. have antibacterial action; Anaerobic bacteria is also had to good effect, as peptococcus, peptostreptococcus, shuttle shape brood cellBacillus, bacteroid (comprising bacteroides fragilis); Most bacterial strains of Pseudomonas aeruginosa, enterococcus and bacillus cloacae are to cephaloWestern fourth is insensitive. Lower respiratory tract, the urogenital of clinical practice due to the anaerobic bacteria of responsive Gram-negative bacteriaThe site infections such as system, abdominal cavity, bone and joint, skin and soft tissue, the internal membrane of heart infects and septicemia. You ShiBe used for aspiration pneumonia, the infection of diabetic's lower limb and abdominal cavity or basin that aerobic bacteria and anaerobic bacteria mixed infection causeInfect in chamber.
Pharmacokinetics is drugs absorption,distribution,metabolism,excretion process and rule in vivoA subject, corresponding to the BA of organism with pharmacodynamic study medicine. Pharmacokinetics sideOverweight the disposal of research body to medicine, but along with the development of subject and the raising of investigative technique level, medicine is to lifeThe effect that the medication disposal system of object as transporter, metabolic enzyme is also belongs to the research category of pharmacokinetics.Medicine disposal characteristic has in vivo determined its drug effect or toxic action intensity to a certain extent, thereby, medicineThing dynamic metabolism research in original new drug research process, have a very important role status and meaning.
In developed countries such as America and Europes, each link that pharmacokinetics research has been researched and developed through original new drug,Comprise before the screening of the structural design of lead compound and optimization, candidate compound and evaluation, drug candidate clinicalEvaluate and clinical research. The practical experience of external recent two decades proves, the moving early stage intervention of specially learning research of drug metabolismTo improve original new drug research and development success rate, reduction R&D costs and risk, accelerate research and development process, reality with system researchThe key point of the existing clinical safety rational use of medicines.
The clinical prodrug dynamic metabolism research of China, is only confined to grinding due to multiple technologies Bottleneck Restrictions with evaluationSend out the later stage some drugs original shape is carried out to preliminary pharmacokinetics evaluation, evaluation content mainly comprises that medicine is formerThe blood plasma of shape through time process, main organs distribute and the descriptive research of the excretion pathway of original shape medicine. Along with China is newMedicine research and development pattern is from taking " copying as main " to " combination of imitation and creation " and the transformation of " innovation is as main ", and China is originalPharmacokinetics research evaluation system can not adapt to the needs that new drug development mode development changes, can not be abundantThe research of performance pharmacokinetics changes in structural design and optimization, new drug dosage form design and the formulation of lead compoundMake, the directive function of the aspect such as drug interaction prediction and clinical safety rational use of medicines.
Than developed countries such as America and Europes, the basic reason that the original pharmacokinetics research and development of China lags behindBe backwardness and the research system imperfection of key technology level. Embody a concentrated reflection of trace in high-sensitivity biological sampleThe quantitative analysis tech of medicine, the fast prediction of inside and outside absorption,distribution,metabolism,excretion characteristic, screens and commentsValency technology, Pharmacokinetics-Pharmacodynamics binding technology, drug interaction prediction and the relevant crucial skills such as assessment techniqueThe shortage of art.
Summary of the invention:
For this reason, accurately study the pharmacokinetic property of Cefoxitin, understand its pharmaceutically-active regularity and poisonProperty produce material base, to instructing the rational dosage regimen of clinical formulation, improve clinical application security and closeRationality has key effect and significance.
Therefore, the object of this invention is to provide a set of clinical prodrug dynamic metabolism key technology and research system existsThe application of Cefoxitin, more accurately to study the absorption,distribution,metabolism,excretion process of Cefoxitin.
Therefore, the invention provides clinical prodrug dynamic metabolism key technology and research system at CefoxitinApplication, it comprises:
(1) certain density Cefoxitin is given after animal used as test certain hour, collect blood, urine and ight soilIn one or more biological samples;
(2) biological sample obtaining in step (1) is adopted to liquid-liquid extraction, albumen precipitation, solid phase extraction techniquesProcess, make corresponding solution;
(3) adopt liquid chromatography-mass spectrography (LC-MS), liquid chromatography-tandem mass spectrometry (LC-MS/MS) to analyzeThe solution of preparation in step (2).
Therefore, the present invention also provides clinical prodrug dynamic metabolism key technology and research system at CefoxitinApplication, it comprises certain density Cefoxitin is given after animal used as test certain hour, collects blood, adoptsHigh-effective affinity chromatography method is measured the combination rate of Cefoxitin and plasma protein.
Therefore, the present invention also provides clinical prodrug dynamic metabolism key technology and research system at CefoxitinApplication, it comprises processes Caco-2 cell by certain density Cefoxitin, detect cellular morphology, resistance value,The permeability of Cefoxitin and alkaline phosphatase activities, to detect permeable membrane and the athrocytosis of Cefoxitin.
Therefore, the present invention also provides clinical prodrug dynamic metabolism key technology and research system at CefoxitinApplication, it comprises that certain density Cefoxitin is processed to whole animal, S9, people's intestines microsome and monoclonal is pureChange enzyme, detect the qualification of Cefoxitin In vitro metabolism stability and metabolite, by conjunction with LC-MS/MS, NMRTechnology is identified the possible I phase of this medicine and II phase metabolite on the basis of quantitative analysis.
The present invention is by providing clinical prodrug dynamic metabolism key technology and research system answering at CefoxitinWith, adopting high flux, high sensitivity quantitation analytical technology, the sensitivity that has improved Cefoxitin, is Related Drug generationProperty research has been established technical foundation. The present invention simultaneously uses new high-effective affinity chromatography method to measure Cefoxitin at notePlasma protein binding rate after penetrating, to detect Cefoxitin absorption, transhipment and distribution character in vivo. Medicine bloodSlurry protein binding rate is the percentage that amount that medicine is combined with plasma protein accounts for medicine total concentration, is drug metabolism powerOne of important parameter of learning; It affects medicine distribution, metabolism and excretion in vivo, thereby affects its action intensityAnd the time, and often closely related with interaction and the mechanism of action etc. of medicine. Therefore, medicine plasma protein knotThe research of closing rate is all significant for instructing clinical rational drug use. In addition, the present invention also uses Caco-2Cell model, evaluates its permeable membrane and athrocytosis. Finally, detected external generation of CefoxitinThank stability and metabolite.
Detailed description of the invention
The invention provides the application at Cefoxitin of clinical prodrug dynamic metabolism key technology and research system,It comprises:
(1) certain density Cefoxitin is given after animal used as test certain hour, collect blood, urine and ight soilIn one or more biological samples;
(2) biological sample obtaining in step (1) is adopted to liquid-liquid extraction, albumen precipitation, solid phase extraction techniquesProcess, make corresponding solution;
(3) adopt liquid chromatography-mass spectrography (LC-MS), liquid chromatography-tandem mass spectrometry (LC-MS/MS) to analyzeThe solution of preparation in step (2).
Experimental animal of the present invention can be rat, mouse, cavy, rabbit or dog.
Described finite concentration and certain hour are determined according to animal used as test.
One preferred embodiment in, in step (2), described liquid-liquid extraction adopts ethyl acetate and ammoniaMixture (for example, the concentration of ammoniacal liquor in mixture is 10%) and ethyl acetate and the NaOH (example of waterAs, the concentration of NaOH in mixture is 0.15M) mixture; Described albumen precipitation employing methanol extraction,The mixture precipitation of acetonitrile precipitation, methyl alcohol and acetonitrile, the volume ratio of methyl alcohol and acetonitrile is for example 1:1.5.
One preferred embodiment in, in step (2), described liquid-liquid extraction adopts ethyl acetate and ammoniaThe mixture of the mixture of water and ethyl acetate and NaOH, described albumen precipitation adopts methanol extraction, acetonitrilePrecipitation, methyl alcohol and acetonitrile precipitation.
One preferred embodiment in, in step (3), by system optimization mobile phase composition, mobile phaseGradient flow velocity, mass spectrum ionization conditions, to improve the sensitivity to Cefoxitin quantitative analysis; And greatly carryHigh analysis throughput, for solid analytical technology basis has been laid in the pharmacokinetics research of Cefoxitin.
One preferred embodiment in, this application also comprises that adopting high-effective affinity chromatography method to measure Cefoxitin existsAfter injection certain hour with the combination rate of plasma protein. Binding of drug to plasma proteins rate is that medicine is combined with plasma proteinAmount account for the percentage of medicine total concentration, be one of important parameter of pharmacokinetics. It affects medicine at bodyIn distribution, metabolism and excretion, thereby affect its action intensity and time, and often with the interaction of medicine andMechanism of action etc. are closely related. Therefore, the research of binding of drug to plasma proteins rate is for instructing clinical rational drug use allSignificant.
One preferred embodiment in, this application also comprises that certain density Cefoxitin is processed to Caco-2 is thinBorn of the same parents, permeability and the alkaline phosphatase activities of detection cellular morphology, resistance value, Cefoxitin, to detect cephalo westThe permeable membrane of fourth and athrocytosis.
One preferred embodiment in, this application also comprise by certain density Cefoxitin process whole animal,S9, people's intestines microsome and monoclonal purifying enzyme detect the qualification of Cefoxitin In vitro metabolism stability and metabolite,By in conjunction with LC-MS/MS, NMR technology, on the basis of quantitative analysis to the possible I phase of Cefoxitin andII phase metabolite is identified. In vitro metabolism stability is the predictive compound important means of biological half-life.External tachymetabolism enzyme qualification and medicine are set up based on intestines microsome technology and recombinant monoclonal P450 zymotechnicMetabolism interaction platform. Elimination speed according to medicine in intestines microsome and close in various and drug metabolismRelevant P450 enzyme hypotype is as special in CYPIA2,2A6,286,2C8,2C9,2C19,2D6,3A4 etc.Property inhibitor exist under elimination speed Research on differences, judge which kind of enzyme hypotype may participate in the metabolism of this medicine. RootAccording to microsome result of study, further using monoclonal enzyme is confirmed, and carry out deep enzyme kinetics parameter withStudy metabolic pathways.
Apply the various and specific inhibitor closely-related CYP450 enzyme of drug metabolism hypotype, intestines are micro-in vitroIn plastochondria system, carry out the preliminary confirmation of drug metabolism phenotype, then select corresponding CYP450 according to PRELIMINARY RESULTSEnzyme hypotype monoclonal enzyme is confirmed. By the binding of two kinds of methods, can reduce greatly research cost, compareStudy in external directly using monoclonal enzyme, the technology has more general, easy and feature cheaply.
Metabolite and medicine drug activity and toxic action is in vivo closely related, by conjunction with LC-MS/MS,The Structural Identification technology such as NMR, on the basis of quantitative analysis to the possible I phase of this medicine and II phase metaboliteIdentify.
The II phase metabolism of medicine is its final process of eliminating and detoxifying normally, and therefore II phase metabolism research is for going deep intoDetoxification processes and the machine-processed tool of understanding disposition mechanism, the especially toxic medicament of medicine are of great significance.The present invention has adopted small intestinal mucosa cytosol and microsome and mixed liquor (S9) thereof to carry out the II phase metabolism of compoundSeries of studies. The present invention adopts to measure corresponding I phase metabolin or former after glycuronidase, sulfatase hydrolysisThe method of shape medicine is carried out the II generation quantitative study that combines.
The present invention also provides clinical prodrug dynamic metabolism key technology and research system answering at CefoxitinWith, it comprises certain density Cefoxitin is given after animal used as test certain hour, collects blood, adopts efficientAffinity chromatography is measured the combination rate of Cefoxitin and plasma protein.
The present invention also provides clinical prodrug dynamic metabolism key technology and research system answering at CefoxitinWith, it comprises processes Caco-2 cell by certain density Cefoxitin, detects cellular morphology, resistance value, cephaloThe permeability of western fourth and alkaline phosphatase activities, to detect permeable membrane and the athrocytosis of Cefoxitin.
The present invention also provides clinical prodrug dynamic metabolism key technology and research system answering at CefoxitinWith, it comprises processes whole animal, S9, people's intestines microsome and monoclonal purifying enzyme by certain density Cefoxitin,Detect the qualification of Cefoxitin In vitro metabolism stability and metabolite, by conjunction with LC-MS/MS, NMR skillArt is identified the possible I phase of this medicine and II phase metabolite on the basis of quantitative analysis.
Clinical prodrug dynamic metabolism key technology provided by the invention and research system be in the application of Cefoxitin,It comprises employing high flux, high sensitivity quantitation analytical technology, uses new high-effective affinity chromatography method to measure cephalo westThe plasma protein binding rate of fourth after injection, uses Caco-2 cell model to enter its permeable membrane and athrocytosisGo the integrated use of evaluating.
Claims (9)
1. clinical prodrug dynamic metabolism key technology and research system are in the application of Cefoxitin, and it comprises:
(1) certain density Cefoxitin is given after animal used as test certain hour, collect blood, urine and ight soilIn one or more biological samples;
(2) biological sample obtaining in step (1) is adopted to liquid-liquid extraction, albumen precipitation, solid phase extraction techniquesProcess, make corresponding solution;
(3) adopt liquid chromatography-mass spectrography (LC-MS), liquid chromatography-tandem mass spectrometry (LC-MS/MS) to analyzeThe solution of preparation in step (2).
2. application according to claim 1, wherein, in step (2), described liquid-liquid extraction adoptsThe mixture of the mixture of ethyl acetate and ammoniacal liquor and ethyl acetate and NaOH, described albumen precipitation adopts firstAlcohol precipitation, acetonitrile precipitation, methyl alcohol and acetonitrile mixture precipitation.
3. application according to claim 1, wherein, in step (3), by system optimization mobile phaseComposition, eluent gradient flow velocity, mass spectrum ionization conditions, to improve the sensitivity to Cefoxitin quantitative analysis.
4. according to the application described in any one in claim 1-3, wherein, this application also comprises the efficient parent of employingWith chromatography determination Cefoxitin after injection certain hour with the combination rate of plasma protein.
5. according to the application described in any one in claim 1-4, wherein, this application also comprises finite concentrationCefoxitin process Caco-2 cell, detect permeability and the alkaline phosphorus of cellular morphology, resistance value, CefoxitinPhytase activity, to detect permeable membrane and the athrocytosis of Cefoxitin.
6. according to the application described in any one in claim 1-5, wherein, this application also comprises finite concentrationCefoxitin process whole animal, S9, people's intestines microsome and monoclonal purifying enzyme detects Cefoxitin In vitro metabolismThe qualification of stability and metabolite, by conjunction with LC-MS/MS, NMR technology, on the basis of quantitative analysisAbove the possible I phase of this medicine and II phase metabolite are identified.
7. clinical prodrug dynamic metabolism key technology and research system are in the application of Cefoxitin, and it comprises oneThe Cefoxitin of determining concentration gives after animal used as test certain hour, collects blood, adopts high-effective affinity chromatography method to measureThe combination rate of Cefoxitin and plasma protein.
8. clinical prodrug dynamic metabolism key technology and research system are in the application of Cefoxitin, and it comprises oneDetermine the Cefoxitin of concentration and process Caco-2 cell, detect cellular morphology, resistance value, Cefoxitin permeability andAlkaline phosphatase activities, to detect permeable membrane and the athrocytosis of Cefoxitin.
9. clinical prodrug dynamic metabolism key technology and research system are in the application of Cefoxitin, and it comprises oneDetermine the Cefoxitin of concentration and process whole animal, S9, people's intestines microsome and monoclonal purifying enzyme, detect CefoxitinThe qualification of In vitro metabolism stability and metabolite, by conjunction with LC-MS/MS, NMR technology, quantitatively pointOn the basis of analysing, the possible I phase of this medicine and II phase metabolite are identified.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108760904A (en) * | 2018-04-08 | 2018-11-06 | 江苏亚邦强生药业有限公司 | A kind of method that plasma sample pretreatment technology combination UPLC-MS/MS measures Cefdinir content in human normal plasma |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108760904A (en) * | 2018-04-08 | 2018-11-06 | 江苏亚邦强生药业有限公司 | A kind of method that plasma sample pretreatment technology combination UPLC-MS/MS measures Cefdinir content in human normal plasma |
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