CN106682396A - Method for establishing PK-PD combination model of four representative components in traditional Chinese medicine formula - Google Patents
Method for establishing PK-PD combination model of four representative components in traditional Chinese medicine formula Download PDFInfo
- Publication number
- CN106682396A CN106682396A CN201611125746.0A CN201611125746A CN106682396A CN 106682396 A CN106682396 A CN 106682396A CN 201611125746 A CN201611125746 A CN 201611125746A CN 106682396 A CN106682396 A CN 106682396A
- Authority
- CN
- China
- Prior art keywords
- kinds
- composition
- prescription
- chinese prescription
- effect
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- G—PHYSICS
- G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
- G16C—COMPUTATIONAL CHEMISTRY; CHEMOINFORMATICS; COMPUTATIONAL MATERIALS SCIENCE
- G16C20/00—Chemoinformatics, i.e. ICT specially adapted for the handling of physicochemical or structural data of chemical particles, elements, compounds or mixtures
- G16C20/30—Prediction of properties of chemical compounds, compositions or mixtures
Landscapes
- Chemical & Material Sciences (AREA)
- Crystallography & Structural Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Bioinformatics & Computational Biology (AREA)
- Computing Systems (AREA)
- Theoretical Computer Science (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
The invention provides a method for establishing a PK-PD combination model of four representative components in a traditional Chinese medicine formula. By means of the liquid chromatography-mass spectrometry method, drug concentrations of the four representative components in plasma samples obtained at different time points after a disease model animal takes a drug are detected, and a drug-time curve is obtained; meanwhile, two drug effect indexes in the obtained plasma samples at different time points are detected by means of kits, and a time-effect curve is obtained; then by the adoption of pharmacokinetic software, pharmacokinetic parameters of the four representative components are subjected to fitting by means of the compartment model analysis method, and a PK parameter is obtained; on this basis, related pharmacokinetic parameters are fixed, the time-effect relation is subjected to fitting, a related PD parameter is obtained, and the PK-PD combination model of the four representative components in the traditional Chinese medicine formula is established according to the PD parameter. The bottleneck of the establishment of the multi-component and multi-target PK-PD combination model of the traditional Chinese medicine is overcome so as to reveal the pharmacodynamic material basis and action mechanism of the traditional Chinese medicine formula.
Description
Technical field
The invention belongs to Chinese materia medica research field, the PK-PD that composition is represented in relating in particular to Chinese prescription combines mould
The method for building up of type；More particularly to the PK-PD that a kind of Chinese prescription for treating cerebral ischemia reperfusion injury represents composition combines mould
The method for building up of type, can be used to set up the PK-PD binding models that composition is represented in Chinese prescription.
Background technology
Pharmacokinetic-Pharmacodynamic (Pharmacokinetic-pharmacodynamic, PK-PD) binding model
It is to study the physiological disposition of medicine, medicine to the effect of body and the important tool of relation therebetween, by PK-PD binding models
Chinese medicine research is applied to, scientific basis can be provided for the effective substance and the mechanism of action that illustrate Chinese medicine.
In recent years, many scholars have done many exploration sex works in the structure of the PK-PD binding models of Chinese medicine, but Chinese medicine
" multicomponent, too many levels, multipath, Mutiple Targets " action character of complex system, determines the PK-PD binding models for carrying out Chinese medicine
Research there is larger difficulty, and there are the following problems：(1) the Chinese medicine pharmacokinetic under morbid state is have ignored,
It is not enough to the meaning understanding of the Chinese medicine PK-PD binding models research under morbid state；(2) Chinese medicine PK-PD binding models grind at present
Study carefully and predominantly stay on single-activity composition and single pharmacodynamics index, the effect that have ignored " multicomponent and the Mutiple Targets " of Chinese medicine is special
Point, the PK-PD binding models research with regard to multicomponent, Mutiple Targets are less.
It is well known that the key for setting up PK-PD models is pharmacodynamics index can quantify, and generally close with obvious dose-effect
The Chinese medicine of system could set up good PK-PD models.However, be all by " multicomponent, many ways as most Chinese medicines play a role
What footpath, Mutiple Targets " were produced, then Chinese prescription is just more complicated.Thus quantifiable index how is selected, and then enable
There is between Chinese prescription effective ingredient significant dose-effect relationship to become the bottleneck that restriction represents the foundation of composition PK-PD models.
The content of the invention
The technical problem to be solved in the present invention is to set up to exist for existing Chinese medicine PK-PD binding models in background technology
Deficiency, there is provided the method for building up of four kinds of PK-PD binding models for representing composition in a kind of Chinese prescription.
In order to solve above-mentioned technical problem, the technical scheme is that：In a kind of Chinese prescription, four kinds represent composition
The method for building up of PK-PD binding models, comprises the following steps：
(1) in Chinese prescription four kinds represent pharmacokinetic of the composition in disease model animals body
Disease model rat is taken, Chinese prescription intervention is orally given, daily 2 times, for three days on end；4th day before first administration
And 5min, 15min, 30min, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h are taken a blood sample by intubation after administration
In the EP pipes of heparinization, centrifugation takes 100 μ L of blood plasma to 0.2mL；Blood obtained by different time points is determined using the method for LC-MS
Four kinds of concentration for representing composition in Chinese prescription in slurry, using pharmacokineticss software, calculates related pharmacokineticss ginseng
Number；
(2) research of pharmacodynamics after Chinese prescription is intervened
Step (1) identical plasma sample is taken, with two kinds of pharmacodynamics indexs in blood plasma obtained by kit measurement different time points
Content, draw Drug-time curve；
(3) four kinds of fittings for representing concentration and effect relation of the composition in effect compartment after Chinese prescription intervention
Four kinds of blood concentration-time data for representing composition in Chinese prescription in step (1) are imported to medicine for power
Learn software to be fitted blood concentration-time data using Semi-compartmentalmodeling instruments, obtain four kinds
Concentration v. time data of the composition in effect compartment is represented, four kinds of effect-site concentrations and effect curve for representing composition are then drawn；
(4) in Chinese prescription four kinds of PK-PD binding models for representing composition foundation
The pharmacokinetic parameter of the representative composition correlation in fixing step (1), intends to time-effect relationship in step (2)
Close, obtain the PD parameters of correlation, according to PD parameters, set up PK-PD binding models.
Preferably, the step (1) the disease model rat refers to cerebral ischemia-reperfusion injury in rats model.
Preferably, the step (1) the Chinese prescription intervention be successfully model 12 hours after gavage give pungent Chinese herbaceous peony lyophilizing
Powder pin, dosage are 12.5mg/kg.
Preferably, the step (1) is for described daily 2 times morning 1 time and afternoon 1 time.
Preferably, described four kinds of the step (1) to represent composition be in scutellarin, breviscapine, peoniflorin and Radix Paeoniae
Ester glycosides.
Preferably, the step (1) the intubation blood sampling refers to Rat Right jugular vein intubation.
Preferably, the step (1) and step (3) the pharmacokineticss software refer to WinNonLin softwares.
Preferably, the described two pharmacodynamics indexs of the step (2) refer to SOD and LDH.
Compared with prior art, the invention has the beneficial effects as follows：It is with disease model as object of study, soft with WinNonLin
Blood concentration-time data are fitted by the Semi-compartmental modeling instruments in part, obtain Chinese medicine group
Fang Zhong represents concentration v. time data of the composition in effect compartment, so can cause Chinese prescription represent composition and pharmacodynamics index it
Between obvious dose-effect relationship is presented, finally set up the PK-PD binding models that Chinese prescription represents composition, to disclose Chinese prescription
Effective substance and its mechanism of action.
Description of the drawings
Fig. 1 is that to represent blood medicine of the composition scutellarin in models of cerebral ischemia-reperfusion injury rat body in pungent Chinese herbaceous peony prescription dense
Degree-time and effect (with SOD as pharmacodynamics index) time plot (n=5)
Fig. 2 is that to represent blood medicine of the composition scutellarin in models of cerebral ischemia-reperfusion injury rat body in pungent Chinese herbaceous peony prescription dense
Degree-time and effect (with LDH as pharmacodynamics index) time plot (n=5)
Fig. 3 is that to represent blood medicine of the composition breviscapine in models of cerebral ischemia-reperfusion injury rat body in pungent Chinese herbaceous peony prescription dense
Degree-time and effect (with SOD as pharmacodynamics index) time plot (n=5)
Fig. 4 is that to represent blood medicine of the composition breviscapine in models of cerebral ischemia-reperfusion injury rat body in pungent Chinese herbaceous peony prescription dense
Degree-time and effect (with LDH as pharmacodynamics index) time plot (n=5)
Fig. 5 is that to represent blood medicine of the composition peoniflorin in models of cerebral ischemia-reperfusion injury rat body in pungent Chinese herbaceous peony prescription dense
Degree-time and effect (with SOD as pharmacodynamics index) time plot (n=5)
Fig. 6 is that to represent blood medicine of the composition peoniflorin in models of cerebral ischemia-reperfusion injury rat body in pungent Chinese herbaceous peony prescription dense
Degree-time and effect (with LDH as pharmacodynamics index) time plot (n=5)
Fig. 7 is to represent blood medicine of the composition lactone glucoside of Radix Paeoniae in models of cerebral ischemia-reperfusion injury rat body in pungent Chinese herbaceous peony prescription
Concentration-time and effect (with SOD as pharmacodynamics index) time plot (n=5)
Fig. 8 is to represent blood medicine of the composition lactone glucoside of Radix Paeoniae in models of cerebral ischemia-reperfusion injury rat body in pungent Chinese herbaceous peony prescription
Concentration-time and effect (with LDH as pharmacodynamics index) time plot (n=5)
Fig. 9 is to represent effect compartment of the composition scutellarin in models of cerebral ischemia-reperfusion injury rat body in pungent Chinese herbaceous peony prescription
Concentration and effect (with SOD as pharmacodynamics index) curve chart (n=5)
Figure 10 is to represent effect of the composition scutellarin in models of cerebral ischemia-reperfusion injury rat body in pungent Chinese herbaceous peony prescription
Room concentration and effect (with LDH as pharmacodynamics index) curve chart (n=5)
Figure 11 is to represent effect of the composition breviscapine in models of cerebral ischemia-reperfusion injury rat body in pungent Chinese herbaceous peony prescription
Room concentration and effect (with SOD as pharmacodynamics index) curve chart (n=5)
Figure 12 is to represent effect of the composition breviscapine in models of cerebral ischemia-reperfusion injury rat body in pungent Chinese herbaceous peony prescription
Room concentration and effect (with LDH as pharmacodynamics index) curve chart (n=5)
Figure 13 is to represent effect compartment of the composition peoniflorin in models of cerebral ischemia-reperfusion injury rat body in pungent Chinese herbaceous peony prescription
Concentration and effect (with SOD as pharmacodynamics index) curve chart (n=5)
Figure 14 is to represent effect compartment of the composition peoniflorin in models of cerebral ischemia-reperfusion injury rat body in pungent Chinese herbaceous peony prescription
Concentration and effect (with LDH as pharmacodynamics index) curve chart (n=5)
Figure 15 is to represent effect of the composition lactone glucoside of Radix Paeoniae in models of cerebral ischemia-reperfusion injury rat body in pungent Chinese herbaceous peony prescription
Answer room concentration and effect (with SOD as pharmacodynamics index) curve chart (n=5)
Figure 16 is to represent effect of the composition lactone glucoside of Radix Paeoniae in models of cerebral ischemia-reperfusion injury rat body in pungent Chinese herbaceous peony prescription
Answer room concentration and effect (with LDH as pharmacodynamics index) curve chart (n=5)
Specific embodiment
Below in conjunction with the accompanying drawings the specific embodiment of the present invention is described further.Here it should be noted that for
The explanation of these embodiments is used to help understand the present invention, but does not constitute limitation of the invention.Additionally, disclosed below
As long as the present invention each embodiment in involved technical characteristic do not constitute conflict each other and can just be mutually combined.
Embodiment 1
(1) in pungent Chinese herbaceous peony prescription four kinds represent composition scutellarin, breviscapine, peoniflorin and lactone glucoside of Radix Paeoniae in cerebral ischemia
Pharmacokinetic in reperfusion injury rat model body
Take the male SD rat of 5 280~300g, fasting 12h, by the hydration chlorine of dosage lumbar injection 10% of 0.35g/kg
Aldehyde is anaesthetized.Cerebral ischemia/reperfusion injury of rats model is prepared using the Longa methods of improvement；After model success, cerebral ischemia is taken
Reperfusion injury rat model, orally gives pungent Chinese herbaceous peony prescription intervention, daily 2 times, for three days on end.4th day before first administration and
After administration, 5min, 15min, 30min, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h take a blood sample 0.2mL in heparin by intubation
In the EP pipes of change, centrifugation takes 100 μ L of blood plasma.Pungent Chinese herbaceous peony group in blood plasma obtained by different time points is determined using the method for LC-MS
Fang Zhongsi kinds represent the concentration of composition (scutellarin, breviscapine, peoniflorin, lactone glucoside of Radix Paeoniae), soft using WinNonLin
Part, calculates scutellarin, breviscapine, peoniflorin, the main medicine of lactone glucoside of Radix Paeoniae for kinetic parameter (table 1).
Four kinds of main pharmacokinetic parameters for representing composition in 1 pungent Chinese herbaceous peony prescription of table
In the pungent Chinese herbaceous peony prescription of HPLC/MS-MS, four kinds represent composition (in scutellarin, breviscapine, peoniflorin, Radix Paeoniae
Ester glycosides) content method：
1) instrument
Waters Acquity UPLC ultrahigh pressure liquid phases-triple level Four bar GC-MS (AcquityTM UPLC-TQD
System, including binary geopressure gradient pump, vacuum degassing machine, automatic sampler, electron spray ionisation source, column oven etc., MassLynx
4.1 mass spectrum work stations)；MTN-2800D nitrogen blows enrichment facility (Tianjin Ao Te Sainzs Instrument Ltd.)；XYN-15LP nitrogen blows
Instrument nitrogen gas generator (Shanghai Xi You Analytical Instrument Co., Ltd)；680 microplate reader (U.S. Bio-Rad)；Water purifier
The special ultrapure water machine of laboratory (water that Water Management Equipment Ltd.)；(German Eppendorf shares are public for micropipettor
Department).
2) prepared by test sample
1. sample treatment：100 μ l of plasma sample, plus 1% formic acid water, 50 μ l are taken, 0.5 μ g/ml puerarins, 15 μ l, whirlpool are mixed, then
Plus 380 μ l of methanol, whirlpool mix, ultrasonic 15min, 12000rpm centrifugation 10min, transfer supernatant into 1.5ml EP pipes, blow in nitrogen
On instrument, 30 DEG C dry up.50% acetonitrile, 150 μ l redissolve, and whirlpool is mixed, ultrasonic 15min, 15000rpm centrifugation 10min, take supernatant and enter
Sample.
2. mark song is processed：100 μ l of blank plasma, plus 1% formic acid water, 50 μ l, 0.5 μ g/ml puerarins internal standard, 15 μ l, whirlpool are mixed,
Plus mixed mark 75 μ l of solution, whirlpool is mixed, plus 305 μ l of methanol, and whirlpool is mixed, ultrasonic 15min, 12000rpm centrifugation 10min, and transfer supernatant is extremely
In 1.5ml EP pipes, 30 DEG C dry up on the Nitrogen evaporator.50% acetonitrile, 150 μ l redissolve, and whirlpool is mixed, ultrasonic 15min, 15000rpm centrifugations
10min, takes supernatant sample introduction.
Chromatograph and Mass Spectrometry Conditions：
Chromatographic condition:Waters Acquity BEH C18 chromatographic columns (2.1mm × 50mm, 1.7 μm)；Column temperature：45 DEG C,
- 0.1% formic acid water gradient elution of 0.1% formic acid acetonitrile, gradient are 0~1min:2~5%；1~3min：5~15%；3~
4min:15~20%；4~5min:20~35%；5~6min:35~90%；7min:5%；Flow velocity is 0.35mLmin-1；
Sampling volume is 3 μ L.
Mass Spectrometry Conditions:Electron spray ionisation source (ESI)；Ion source temperature：150℃；Capillary voltage：2.9kV；Remove solvent gas
Temperature：400℃；Collision gas are Ar (0.16mLmin-1)；Solvent gas are gone to be N2 (800Lh-1)；Scan mode is many reactions
Ion monitoring mode (MRM).Scutellarin：M/z 463, breviscapine：M/z 447, peoniflorin：M/z 525.2, peony lactone
Glycosides：M/z 481.1, puerarin：m/z 417.0.
(2) research of pharmacodynamics after pungent Chinese herbaceous peony prescription is intervened
Step (1) identical plasma sample is taken, with two kinds of pharmacodynamics indexs in blood plasma obtained by kit measurement different time
The content of (SOD and LDH), with reference to the plasma drug concentration data of step (1), draws four kinds respectively and represents composition (scutellarin, oil lamp
A prime, peoniflorin, lactone glucoside of Radix Paeoniae) blood concentration-time and effect (respectively with SOD and LDH as the pharmacodynamics index) time it is bent
Line chart (Fig. 1, Fig. 2, Fig. 3, Fig. 4, Fig. 5, Fig. 6, Fig. 7 and Fig. 8).
(3) in pungent Chinese herbaceous peony prescription four kinds represent composition (scutellarin, breviscapine, peoniflorin, lactone glucoside of Radix Paeoniae) in effect
The fitting of room concentration
Composition (scutellarin, breviscapine, peoniflorin, Radix Paeoniae are represented four kinds in the pungent Chinese herbaceous peony prescription in step (1) respectively
Lactone glycoside) blood concentration-time data import to WinNonLin softwares, then using Semi-compartmental
Modeling instruments are fitted to blood concentration-time data, obtain scutellarin, breviscapine, peoniflorin, peony lactone
Concentration v. time data of the glycosides in effect compartment, then draws scutellarin, breviscapine, peoniflorin, the effect compartment of lactone glucoside of Radix Paeoniae
Concentration and effect (respectively with SOD and LDH as pharmacodynamics index) curve (Fig. 9, Figure 10, Figure 11, Figure 12, Figure 13, Figure 14, Tu15He
Figure 16).
(4) foundation of the PK-PD binding models of composition scutellarin is represented in pungent Chinese herbaceous peony prescription
The relevant pharmacokinetic parameter of the scutellarin in fixing step (1), using the PK- in WinNonLin softwares
When PD model are in step (2), m- effect (respectively with SOD and LDH as pharmacodynamics index) relation is fitted, and obtains correlation
PD parameters, and then the parameter of the PK-PD binding models of scutellarin in pungent Chinese herbaceous peony prescription is obtained, wherein scutellarin is with SOD as medicine
The PK-PD parametric results of effect index are shown in Table 2, and the PK-PD parametric results with LDH as pharmacodynamics index are shown in Table 3.
PK-PD parameter of the composition scutellarin with SOD as pharmacodynamics index is represented in 2 pungent Chinese herbaceous peony prescription of table
PK-PD parameter of the composition scutellarin with LDH as pharmacodynamics index is represented in 3 pungent Chinese herbaceous peony prescription of table
According to the PK-PD parameters that composition scutellarin is represented in pungent Chinese herbaceous peony prescription, when with SOD as pharmacodynamics index, can obtain pungent
The PK-PD models of composition scutellarin are represented in Chinese herbaceous peony prescription as:
E=21.08+ (5.49*Ce)/(Ce+7368.24)
When with LDH as pharmacodynamics index, the PK-PD models of composition scutellarin are represented during pungent Chinese herbaceous peony prescription can be obtained as:
E=211.98- (89.13*Ce)/(Ce+2013.2)
Can be extrapolated according to the concentration that composition scutellarin is represented in pungent Chinese herbaceous peony prescription by above PK-PD model corresponding
Drug effect value, it is also possible to which corresponding concentration is calculated according to drug effect value.
Embodiment 2
According to the method for embodiment 1, difference is the PK-PD binding models that composition breviscapine is represented in pungent Chinese herbaceous peony prescription
Set up.
The relevant pharmacokinetic parameter of the breviscapine in fixing step (1), using the PK- in WinNonLin softwares
When PD model are in step (2), m- effect (respectively with SOD and LDH as pharmacodynamics index) relation is fitted, and obtains correlation
PD parameters, and then the parameter of the PK-PD binding models of breviscapine in pungent Chinese herbaceous peony prescription is obtained, wherein breviscapine is with SOD as medicine
The PK-PD parametric results of effect index are shown in Table 4, and the PK-PD parametric results with LDH as pharmacodynamics index are shown in Table 5.
PK-PD parameter of the composition breviscapine with SOD as pharmacodynamics index is represented in 4 pungent Chinese herbaceous peony prescription of table
PK-PD parameter of the composition breviscapine with LDH as pharmacodynamics index is represented in 5 pungent Chinese herbaceous peony prescription of table
According to the PK-PD parameters that composition breviscapine is represented in pungent Chinese herbaceous peony prescription, when with SOD as pharmacodynamics index, can obtain pungent
The PK-PD models of composition breviscapine are represented in Chinese herbaceous peony prescription as:
E=20.67+ (1.22*Ce)/(Ce+5.58)
When with LDH as pharmacodynamics index, the PK-PD models of composition breviscapine are represented during pungent Chinese herbaceous peony prescription can be obtained as:
E=214.17- (32.72*Ce)/(Ce+0.08)
Can be extrapolated according to the concentration that composition breviscapine is represented in pungent Chinese herbaceous peony prescription by above PK-PD model corresponding
Drug effect value, it is also possible to which corresponding concentration is calculated according to drug effect value.
Embodiment 3
According to the method for embodiment 1, difference is that the PK-PD binding models that composition peoniflorin is represented in pungent Chinese herbaceous peony prescription are built
It is vertical.
Pungent Chinese herbaceous peony prescription in fixing step (1) represents the relevant pharmacokinetic parameter of composition peoniflorin, adopts
When PK-PD model in WinNonLin softwares are in step (2), m- effect (respectively with SOD and LDH as pharmacodynamics index) is closed
System is fitted, and the PK-PD binding models of composition peoniflorin are represented in obtaining the PD parameters of correlation, and then the pungent Chinese herbaceous peony prescription of acquisition
The PK-PD parametric results of parameter, wherein peoniflorin with SOD as pharmacodynamics index are shown in Table 6, the PK-PD parameters with LDH as pharmacodynamics index
The results are shown in Table 7.
PK-PD parameter of the composition peoniflorin with SOD as pharmacodynamics index is represented in 6 pungent Chinese herbaceous peony prescription of table
PK-PD parameter of the composition peoniflorin with LDH as pharmacodynamics index is represented in 7 pungent Chinese herbaceous peony prescription of table
According to the PK-PD parameters that composition peoniflorin is represented in pungent Chinese herbaceous peony prescription, when with SOD as pharmacodynamics index, pungent Chinese herbaceous peony can be obtained
The PK-PD models of composition peoniflorin are represented in prescription as:
E=20.02+ (1.58*Ce)/(Ce+0.02)
When with LDH as pharmacodynamics index, the PK-PD models of composition peoniflorin are represented during pungent Chinese herbaceous peony prescription can be obtained as:
E=216.83- (37.31*Ce)/(Ce+0.04)
Corresponding medicine can be extrapolated according to the concentration that composition peoniflorin is represented in pungent Chinese herbaceous peony prescription by above PK-PD model
Valid value, it is also possible to which corresponding concentration is calculated according to drug effect value.
Embodiment 4
According to the method for embodiment 1, difference is the PK-PD binding models that composition lactone glucoside of Radix Paeoniae is represented in pungent Chinese herbaceous peony prescription
Foundation.
Pungent Chinese herbaceous peony prescription in fixing step (1) represents the relevant pharmacokinetic parameter of composition lactone glucoside of Radix Paeoniae, adopts
When PK-PD model in WinNonLin softwares are in step (2), m- effect (respectively with SOD and LDH as pharmacodynamics index) is closed
System is fitted, and obtains the PD parameters of correlation, and then the PK-PD of composition lactone glucoside of Radix Paeoniae is represented in obtaining pungent Chinese herbaceous peony prescription combining mould
The PK-PD parametric results of the parameter of type, wherein lactone glucoside of Radix Paeoniae with SOD as pharmacodynamics index are shown in Table 8, with LDH as pharmacodynamics index
PK-PD parametric results are shown in Table 9.
PK-PD parameter of the composition lactone glucoside of Radix Paeoniae with SOD as pharmacodynamics index is represented in 8 pungent Chinese herbaceous peony prescription of table
PK-PD parameter of the composition lactone glucoside of Radix Paeoniae with LDH as pharmacodynamics index is represented in 9 pungent Chinese herbaceous peony prescription of table
According to the PK-PD parameters that composition lactone glucoside of Radix Paeoniae is represented in pungent Chinese herbaceous peony prescription, when with SOD as pharmacodynamics index, can obtain
The PK-PD models of composition lactone glucoside of Radix Paeoniae are represented in pungent Chinese herbaceous peony prescription as:
E=21.04+ (7.16*Ce)/(Ce+372.4)
When with LDH as pharmacodynamics index, the PK-PD models of composition lactone glucoside of Radix Paeoniae are represented during pungent Chinese herbaceous peony prescription can be obtained as:
E=216.83- (37.31*Ce)/(Ce+0.04)
Can be extrapolated according to the concentration that composition lactone glucoside of Radix Paeoniae is represented in pungent Chinese herbaceous peony prescription by above PK-PD model corresponding
Drug effect value, it is also possible to corresponding concentration is calculated according to drug effect value.
Four kinds of PK-PD moulds for representing composition (scutellarin, breviscapine, peoniflorin, lactone glucoside of Radix Paeoniae) in pungent Chinese herbaceous peony prescription
The result of type shows that concentration and the concentration of scutellarin, breviscapine, peoniflorin, lactone glucoside of Radix Paeoniae of SOD and LDH have one
Fixed dependency.Thus can speculate in pungent Chinese herbaceous peony prescription and its main active scutellarin, breviscapine, peoniflorin, Radix Paeoniae
Ester glycosides can be realized protecting cerebral ischemia reperfusion injury by improving SOD, reduction LDH performance antioxidations.
Embodiments of the present invention are explained in detail above in association with accompanying drawing, but the invention is not restricted to described enforcement
Mode.For a person skilled in the art, in the case of without departing from the principle of the invention and spirit, to these embodiments
Various changes, modification, replacement and modification are carried out, is still fallen within protection scope of the present invention.
Claims (8)
1. in a kind of Chinese prescription four kinds of PK-PD binding models for representing composition method for building up, it is characterised in that including following
Step：
(1) in Chinese prescription four kinds represent pharmacokinetic of the composition in disease model animals body
Disease model rat is taken, Chinese prescription intervention is orally given, daily 2 times, for three days on end；4th day before first administration and
After administration, 5min, 15min, 30min, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h are taken a blood sample by intubation
In the EP pipes of heparinization, centrifugation takes 100 μ L of blood plasma to 0.2mL；Blood obtained by different time points is determined using the method for LC-MS
Four kinds of concentration for representing composition in Chinese prescription in slurry, using pharmacokineticss software, calculates related pharmacokineticss ginseng
Number；
(2) research of pharmacodynamics after Chinese prescription is intervened
Take step (1) identical plasma sample, contained with two kinds of pharmacodynamics indexs in blood plasma obtained by kit measurement different time points
Amount, draws Drug-time curve；
(3) four kinds of fittings for representing concentration and effect relation of the composition in effect compartment after Chinese prescription intervention
Four kinds of blood concentration-time data for representing composition in Chinese prescription in step (1) are imported to pharmacokineticss soft
Part is fitted to blood concentration-time data using Semi-compartmentalmodeling instruments, obtains four kinds of representatives
Concentration v. time data of the composition in effect compartment, then draws four kinds of effect-site concentrations and effect curve for representing composition；
(4) in Chinese prescription four kinds of PK-PD binding models for representing composition foundation
The pharmacokinetic parameter of the representative composition correlation in fixing step (1), is fitted to time-effect relationship in step (2),
The PD parameters of correlation are obtained, according to PD parameters, PK-PD binding models is set up.
2. according to claim 1 in Chinese prescription four kinds of PK-PD binding models for representing composition method for building up, its feature
It is that disease model rat refers to cerebral ischemia-reperfusion injury in rats model described in the step (1).
3. according to claim 1 in Chinese prescription four kinds of PK-PD binding models for representing composition method for building up, its feature
Be, Chinese prescription intervention described in the step (1) be successfully model 12 hours after gavage give pungent Chinese herbaceous peony freeze-dried powder, be administered
Dosage is 12.5mg/kg.
4. according to claim 1 in Chinese prescription four kinds of PK-PD binding models for representing composition method for building up, its feature
It described in the step (1) is for daily 2 times morning 1 time and afternoon 1 time to be.
5. according to claim 1 in Chinese prescription four kinds of PK-PD binding models for representing composition method for building up, its feature
It is that it is scutellarin, breviscapine, peoniflorin and lactone glucoside of Radix Paeoniae that described in the step (1), four kinds represent composition.
6. according to claim 1 in Chinese prescription four kinds of PK-PD binding models for representing composition method for building up, its feature
It is that the blood sampling of intubation described in the step (1) refers to Rat Right jugular vein intubation.
7. according to claim 1 in Chinese prescription four kinds of PK-PD binding models for representing composition method for building up, its feature
It is that pharmacokineticss software refers to WinNonLin softwares described in the step (1) and step (3).
8. according to claim 1 in Chinese prescription four kinds of PK-PD binding models for representing composition method for building up, its feature
It is that two kinds of pharmacodynamics indexs refer to SOD and LDH described in the step (2).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611125746.0A CN106682396A (en) | 2016-12-09 | 2016-12-09 | Method for establishing PK-PD combination model of four representative components in traditional Chinese medicine formula |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611125746.0A CN106682396A (en) | 2016-12-09 | 2016-12-09 | Method for establishing PK-PD combination model of four representative components in traditional Chinese medicine formula |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN106682396A true CN106682396A (en) | 2017-05-17 |
Family
ID=58867915
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201611125746.0A Pending CN106682396A (en) | 2016-12-09 | 2016-12-09 | Method for establishing PK-PD combination model of four representative components in traditional Chinese medicine formula |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106682396A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114295753A (en) * | 2021-12-30 | 2022-04-08 | 贵州医科大学 | Animal model construction method for corium versicolor drug pharmacokinetics and tissue distribution |
| CN117334261A (en) * | 2023-10-15 | 2024-01-02 | 中国中医科学院中药研究所 | Method for establishing integral PK-PD model of multiple cardiotonic effect components |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040157778A1 (en) * | 1999-05-11 | 2004-08-12 | Wing Cheung | Pharmacokinetic and pharmacodynamic modeling of erythropoietin administration |
| CN101046831A (en) * | 2006-03-31 | 2007-10-03 | 上海中医药大学 | Setting, computing method of Chinese medicine multi-component PK-PD combined mathematical module and software fit |
| CN102183608A (en) * | 2011-02-27 | 2011-09-14 | 浙江大学 | Traditional Chinese medicine pharmacokinetics-pharmacodynamics combined analysis method |
| CN103077295A (en) * | 2011-10-25 | 2013-05-01 | 复旦大学附属华山医院 | Method for externally simulating oral administration pharmacokinetics (PK) model based on flow velocity regulation |
-
2016
- 2016-12-09 CN CN201611125746.0A patent/CN106682396A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040157778A1 (en) * | 1999-05-11 | 2004-08-12 | Wing Cheung | Pharmacokinetic and pharmacodynamic modeling of erythropoietin administration |
| CN101046831A (en) * | 2006-03-31 | 2007-10-03 | 上海中医药大学 | Setting, computing method of Chinese medicine multi-component PK-PD combined mathematical module and software fit |
| CN102183608A (en) * | 2011-02-27 | 2011-09-14 | 浙江大学 | Traditional Chinese medicine pharmacokinetics-pharmacodynamics combined analysis method |
| CN103077295A (en) * | 2011-10-25 | 2013-05-01 | 复旦大学附属华山医院 | Method for externally simulating oral administration pharmacokinetics (PK) model based on flow velocity regulation |
Non-Patent Citations (1)
| Title |
|---|
| KENNETH G. KOWALSKI 等: "A Semicompartmental Modeling Approach for", 《JOURNAL OF PHARMACOKINETICS AND BIOPHARMACEUTICS》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114295753A (en) * | 2021-12-30 | 2022-04-08 | 贵州医科大学 | Animal model construction method for corium versicolor drug pharmacokinetics and tissue distribution |
| CN117334261A (en) * | 2023-10-15 | 2024-01-02 | 中国中医科学院中药研究所 | Method for establishing integral PK-PD model of multiple cardiotonic effect components |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Xue et al. | Screening for in vitro metabolites of Abelmoschus manihot extract in intestinal bacteria by ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry | |
| CN102539553B (en) | Method for establishing fingerprint spectrum of liver-enhancing medicine | |
| Chang et al. | Simultaneous determination and pharmacokinetic study of six flavonoids from Fructus Sophorae extract in rat plasma by LC–MS/MS | |
| Fu et al. | Chemical and metabolic analysis of Achyranthes bidentate saponins with intestinal microflora-mediated biotransformation by ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry coupled with metabolism platform | |
| CN102617745B (en) | Preparation method and blood sugar lowering function of Ganoderma lucidum karst polysaccharide F31 | |
| Wen et al. | Identification of metabolites of Buyang Huanwu decoction in rat urine using liquid chromatography–quadrupole time-of-flight mass spectrometry | |
| Shen et al. | Rapid quantification of four major bioactive alkaloids in Corydalis decumbens (Thunb.) Pers. by pressurised liquid extraction combined with liquid chromatography-triple quadrupole linear ion trap mass spectrometry | |
| Zhang et al. | Chemical profile-and pharmacokinetics-based investigation of the synergistic property of platycodonis radix in traditional Chinese medicine formula Shengxian decoction | |
| CN106682396A (en) | Method for establishing PK-PD combination model of four representative components in traditional Chinese medicine formula | |
| CN110187020A (en) | Astragalus root components evaluation method based on treatment atrophic gastritis spectrum effect relationship | |
| CN103191289B (en) | Synchronous preparation method of four effective parts in medicine pair of common anemarrhena rhizome and amur corktree bark and application thereof | |
| Zhang et al. | The comparative pharmacokinetic study of Yuanhu Zhitong prescription based on five quality-markers | |
| CN105572284A (en) | Analysis method for quickly detecting and identifying chemical components in gelsemium elegans | |
| Li et al. | Pharmacokinetics and metabolism study of isoboldine, a major bioactive component from Radix Linderae in male rats by UPLC–MS/MS | |
| CN104059080A (en) | Preparation method of monomer component Hypholomine B in Phellinus igniarius | |
| Wang et al. | Pharmacokinetics and bioavailability of gentiopicroside from decoctions of Gentianae and Longdan Xiegan Tang after oral administration in rats—Comparison with gentiopicroside alone | |
| Ji et al. | Global identification and quantitative analysis of representative components of Xin-Nao-Kang Capsule, a traditional Chinese medicinal formula, by UHPLC-Q-TOF-MS and UHPLC-TQ-MS | |
| Wang et al. | Simultaneous determination of six hydrophilic components in rat plasma after oral administration of Jitai tablet by liquid chromatography–electrospray ionization–tandem mass spectrometry: Application to a pharmacokinetic study | |
| CN102539599B (en) | Method for detecting liver-enhancing medicine | |
| CN105092744A (en) | Characteristic spectrum of total flavonoid extracts in snowbellleaf tickclover herbs as well as establishment method and application of characteristic spectrum | |
| Wang et al. | The profiling of the metabolites of hirsutine in rat by ultra-high performance liquid chromatography coupled with linear ion trap Orbitrap mass spectrometry: An improved strategy for the systematic screening and identification of metabolites in multi-samples in vivo | |
| Liu et al. | The metabolites of Ambinine, a benzo [c] phenanthridine alkaloid, in rats identified by ultra-performance liquid chromatography–quadrupoletime-of-flight mass spectrometry (UPLC/Q-TOF-MS/MS) | |
| Luo et al. | Validated LC-MS/MS method for simultaneous quantification of seven components of Naodesheng in rat serum after oral administration and its application to a pharmacokinetic study | |
| CN113917031B (en) | Method for determining blood concentration of lung-tonifying and blood-activating capsule in vivo by UHPLC-MS/MS method | |
| Huo et al. | Tentative identification of new metabolites of cnidilin by liquid chromatography–mass spectrometry |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20170517 |