CN104897791B - A kind of Chinese medicines is for dynamic (dynamical) curve simulation and Forecasting Methodology - Google Patents
A kind of Chinese medicines is for dynamic (dynamical) curve simulation and Forecasting Methodology Download PDFInfo
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Abstract
A kind of Chinese medicines is for dynamic (dynamical) curve simulation and Forecasting Methodology.It passes through some steps, finds that the composition similar with confirming chemical constitution has similar change of pharmacokinetics, the most similar Γ after the complex system of oral Chinese medicine prescription+Value;Then, at known composition A at the Γ in each moment+Value, it was predicted that the AUC time graph of other structure analogous components, thus set up pharmacokinetics prediction new approaches and method, the method can be used for the prediction of the pharmacokinetics of the structurally similar compounds of single medicinal material or Chinese medicine compound.Specifically include following steps: 1, composition A is obtained respectively its time front of blood concentration in single medicinal material and compound medicines;2, its AUC time changing curve is obtained;3, the AUC sum in each moment and the ratio Γ of meansigma methods are calculated+;4, composition B is done the cluster analysis of chemically based structural similarity;If 5, belonging to a class, the AUC time graph of the most measurable composition B together according to cluster analysis result composition B and composition A.
Description
Technical field
The present invention relates to a kind of Chinese medicines for dynamic (dynamical) curve simulation and Forecasting Methodology and system thereof, specifically, relate to
And AUC (area under the time graph)-time graph of a kind of composition in simulation single medicinal material and compound recipe, and predict another kind of composition
AUC-time graph in single medicinal material and compound recipe.
Background technology
Chinese medicine is complicated chemical system, there is the drug-drug interactions of complexity, in monomer component being administered orally and being administered orally
, even if its oral dose is just the same, the biggest difference can be there is between the two in recurrence due to taking drug square preparation.But, the property that ADME is relevant
Matter prediction is all derived from high-throughout monomeric compound, is used for predicting the ADME character of monomeric compound with they modelings.But
It is, because Chinese medicine compound exists complicated drug-drug interactions, so these forecast models are for traditional Chinese medicine complex system not
It is suitable for, needs new Research Thinking, set up new forecast model and method.
The information being disclosed in this background section is merely intended to deepen the understanding of the general background technology to the present invention, and
It is not construed as recognizing or implying the prior art that this information structure is the most known to those skilled in the art in any form.
Summary of the invention
In the present invention, a kind of new predicting strategy and forecast model are proposed, as follows: Chinese medicine compound compound,
According to chemical constitution similarity score, it is divided into different classifications, of a sort compound, is considered structure and is similar to.Compound is tied
The compound that structure is similar, may act on identical target, shows similar physicochemical property, pharmacokinetic property and pharmacology and lives
Property, to this end, propose a hypothesis, it may be assumed that oral Chinese medicine compound preparation, wherein, the compound that structure is similar, possible similar metabolism
Risk, so, for compound Chinese medicinal preparation, can be dense by obtaining one or a few compound blood medicine in vivo
Degree-time graph, thus predict other compounds blood concentration-time curve in vivo, thus obtain Related Drug for power
Learn parameter, provide new approaches for Chinese medicine compound pharmacokinetics.
To this end, the invention provides a kind of Chinese medicines for dynamic (dynamical) curve simulation and Forecasting Methodology, can be used for single medicinal material
Or the prediction of the pharmacokinetics of the structurally similar compounds of Chinese medicine compound, it passes through some steps, finds and confirm chemistry
The similar composition of structure has similar change of pharmacokinetics, the most similar Γ after the complex system of oral Chinese medicine prescription+
Value;Then, at known composition A at the Γ in each moment+Value, it was predicted that the AUC-time graph of other structure analogous components, thus build
Vertical pharmacokinetics prediction new approaches and method.
Specifically, the method includes:
Step 1. obtains its blood concentration-time curve in single medicinal material and compound medicines respectively to composition A;
Step 2. calculating composition A is the face under each blood concentration-time curve measuring the moment in single medicinal material and compound medicines
Long-pending AUC, and then obtain its AUC-time changing curve;
Step 3. calculating composition A is the AUC sum in each moment and the ratio Γ of meansigma methods in single medicinal material and compound medicines+, its
Computing formula is as follows:
Wherein, xA(ti)、yA(ti) it is respectively composition A AUC in i-th moment in compound medicines and single medicinal material;
Composition B is done the cluster analysis of chemically based structural similarity by step 4.;
If step 5. belongs to a class together according to cluster analysis result composition B and composition A, then can be at known composition A in each moment
Γ+Value, composition B AUC in single medicinal material (or compound medicines) and the 3rd hour (i.e. t in compound medicines (or single medicinal material) thereof7Time
Carve) AUC in the case of, it was predicted that composition B is the 4th hour (i.e. t in compound medicines (or single medicinal material)8Moment) and later AUC-
Time graph, that is
Or
Wherein, xB(ti)、yB(ti) it is respectively composition B AUC in i-th moment in compound medicines and single medicinal material.
In described step 1, obtain composition A in single medicinal material and compound recipe by high performance liquid chromatography mass spectrum/mass spectrometry
Blood concentration-time curve.
When testing blood drug level, selection formic acid water-methanol is as flowing phase, and uses electro-spray ionization source ESI,
Positive ion mode detects, and medicine ion concentration is measured by many reaction detection MRM pattern.
When testing blood drug level, use protein precipitation method in sample pre-treatments.
In described step 2 by trapezoidal method calculate composition A in single medicinal material and compound recipe each time point blood drug level-
Area under time graph, described trapezoidal method computing formula is as follows:
Wherein, A (ti) be in compound recipe and single medicinal material composition A at the AUC in the i-th moment, C (ti) it is in compound recipe and single medicinal material
Composition A is at the blood drug level in the i-th moment, and t0=0, A (0)=0, C (0)=0.
Methods and apparatus of the present invention has further feature and advantage, and these further features and advantage are by from being hereby incorporated by
It is clear that or state in detail in the drawings and specific embodiments, accompanying drawing and concrete in accompanying drawing and detailed description below
Embodiment is provided commonly for explaining some principle of the present invention.
Accompanying drawing explanation
Description by carrying out below with reference to accompanying drawing is manifested, described by other features and advantages of the present invention
In accompanying drawing:
Figure 1A, Figure 1B and Fig. 1 C shows that corydaline (I), α-allocryptopine (II), tetrahydropalmatine (III), tetrahydrochysene are little respectively
Bark of a cork tree alkali (IV), imperatorin (V), isoimperatorin (VI), byak-angelicin (VII), warfarin sodium (VIII, IS) and promethazine hydrochloride
The blank plasma samples chromatogram of (Ⅸ, IS), blank plasma standard are added LLOQ chromatogram and are administered the blood plasma sample after 2 hours
Product chromatogram;
Fig. 2 is the mean blood plasma concentration-time plot (n=6) of α-allocryptopine after SD Oral Administration in Rats difference extract;
Fig. 3 is the mean blood plasma concentration-time plot (n=6) of tetrahydropalmatine after SD Oral Administration in Rats difference extract;
Fig. 4 is the mean blood plasma concentration-time plot (n=6) of N-1 after SD Oral Administration in Rats difference extract;
Fig. 5 is the mean blood plasma concentration-time plot (n=6) of corydaline after SD Oral Administration in Rats difference extract;
Fig. 6 is the mean blood plasma concentration-time plot (n=6) of byak-angelicin after SD Oral Administration in Rats difference extract;
Fig. 7 is the mean blood plasma concentration-time plot (n=6) of imperatorin after SD Oral Administration in Rats difference extract;
Fig. 8 is the mean blood plasma concentration-time plot (n=6) of isoimperatorin after SD Oral Administration in Rats difference extract;
Fig. 9 shows 7 composition cluster analyses in Yuanhu Zhitong Prescription based on chemical constitution similarity score between any two
Result;
Figure 10 shows 7 compositions AUC-time changing curve in single medicinal material and compound recipe;
Figure 11 shows the result of 7 composition cluster analyses in Yuanhu Zhitong Prescription based on the change of AUC-time graph;
Figure 12 shows the Γ of 7 compositions+The scatterplot of value.
Detailed description of the invention
Specific reference will be made to now each embodiment of the present invention, these are implemented with shown in description below in the accompanying drawings
The example of scheme.Although the present invention combines with exemplary and is described, it will be appreciated that this specification not purport
Limiting the invention to those exemplary.On the contrary, it is contemplated that not only cover these exemplary,
And cover and can be included in various replacements within the spirit and scope of the present invention being defined by the appended claims, repair
Change, equivalents and other embodiment.
In the Chinese medicines of the present invention is for dynamic (dynamical) curve simulation and Forecasting Methodology, initially set up in Yuanhu Zhitong Prescription 7
Individual main active analysis in vivo.
Yuanhu Zhitong Prescription is mainly made up of Rhizoma Corydalis and the Radix Angelicae Dahuricae two taste medicine, is mainly composed of alkaloids chemical combination in Rhizoma Corydalis
Thing, and the Radix Angelicae Dahuricae is mainly composed of coumarin kind compound, the pharmacokinetic aspect to two medicines, domestic and foreign literature is most
Concentrate on the assay to tetrahydropalmatine, but the feature of Chinese medicine is multicomponent to play a role jointly, investigates other compositions
Content in vivo is the most extremely necessary.In order to be better understood from the Pharmacological Mechanism of Yuanhu Zhitong Prescription, physiological disposition,
It is necessary set up a kind of sensitive and analyze method accurately, to measure in biological sample (such as blood plasma, tissue homogenate and urine)
The content of main component.
Little by setting up α-allocryptopine of measuring in rat plasma sample, tetrahydropalmatine, tetrahydrochysene simultaneously in the present invention
The LC-MS-MS method of 7 kinds of main components such as bark of a cork tree alkali, corydaline, byak-angelicin, imperatorin, isoimperatorin.
Experimental apparatus used in the present invention:
Waters Acquity UPLC System, Waters Quattro Premier XE, the water generation limited public affairs of science and technology
Department);MIKRO 220R type centrifuge, Hettich company of Germany;
MX-S type turbine mixer, SCILOGEX company of the U.S.;
XS205 type analysis balance, Switzerland's prunus mume (sieb.) sieb.et zucc. Teller-torr benefit Instrument Ltd..
Medicine used in the present invention and reagent:
Acetonitrile (chromatographically pure, Merck company);
Methanol (chromatographically pure, Merck company);
α-allocryptopine (Mei He bio tech ltd of Shenzhen, lot number: 20100318, purity: 98%);
Tetrahydropalmatine (National Institute for Food and Drugs Control, lot number: 110726-201011, purity 99.9%);
Corydaline (sigma, lot number: S449121, purity: 98%);
N-1 (above Hiroad standing grain medical sci-tech Development Co., Ltd, lot number: 100516, purity: 98%);
Byak-angelicin (Pusi Biological Science & Technology Co., Ltd., Chengdu, lot number: RFS-B-100610-04, purity 99.9%);
Isoimperatorin (National Institute for Food and Drugs Control, lot number: 110827-200407, purity: 98%);
Imperatorin (National Institute for Food and Drugs Control, lot number: 110826-200712, purity: 99.9%).
Medical material used in the present invention:
The Radix Angelicae Dahuricae (Angelica Dahurica (Fisch.ex Hoffm.) Benth.et Hook.f.) originates from Hebei province;
Rhizoma Corydalis (Corydalis yanhusuoW.T.Wang) originates from Hangzhou,
All it is purchased from Anguo Chinese crude drug company limited of Hebei province, by what uncommon flourish pharmacist's mirror of Institute Of Chinese Materia Medica Of China Academy of Chinese Medical Sciences
It is set to medical material certified products.
Laboratory animal used in the present invention:
SD rat, male, body weight 230 ± 20g, Laboratory Animal Science portion of Department Of Medicine, Peking University provide, the quality certification number:
SCXK (capital) 2009-0017.At temperature 20-22 DEG C, relative humidity 45%-65%, raise under the conditions of illumination/dark 12h/12h,
Free diet, drinking-water, adaptability starts experiment after raising 3 days.
The preparation of the standard solution that Fa Benming is used:
Precision weighs α-allocryptopine, tetrahydropalmatine, N-1, corydaline, byak-angelicin, imperatorin respectively
It is dissolved in methanol with isoimperatorin, is made into Stock concentrations and is respectively 1mg/mL, it is different dense that storing solution methanol dilution is become
The mixed solution of degree, respectively containing α-allocryptopine, N-1 0.5,1,2.5,5,25,50,100 and 250ng/ml, containing prolonging
Rhizoma Corydalis B prime and corydaline 1,2,5,10,50,100,200 and 500ng/ml, containing byak-angelicin, imperatorin and isoimperatorin
The standard solution of 2,4,10,20,100,200 and 400 and 1000ng/ml, for the preparation of standard curve.
Precision weighs internal standard warfarin sodium and promethazine hydrochloride is dissolved in methanol and is configured to the storing solution of 100 μ g/mL, the dilutest
It is interpreted as 50ng/mL and 25ng/mL standard solution.It is standby that all solution are placed in-20 DEG C of Refrigerator stores.
Plasma sample standard curve used in the present invention and the preparation of Quality Control (QC) sample:
Take rat blank plasma 50 μ l, add hybrid standard serial solution 50 μ l, be configured to be equivalent to α-allocryptopine with
Final concentration of 0.5,1,2.5,5,25,50, the 100 of N-1 and 250ng/ml, tetrahydropalmatine is dense with the end of corydaline
Degree is 1,2,5,10,50,100,200 and 500ng/ml, byak-angelicin, imperatorin and isoimperatorin final concentration of 2,4,
10,20,100,200,400 and the correcting sample of 1000ng/ml, in addition to being not added with methanol, remaining presses " plasma sample pre-treatment " item
Lower operation.
QC sample is with method dilution preparation, and concentration is respectively as follows: α-allocryptopine and N-1 be 1,100,200ng/
Ml, tetrahydropalmatine and corydaline be 2,200,400ng/ml, byak-angelicin, imperatorin and isoimperatorin be 4,400,
800ng/ml。
Chromatograph mass spectrum analysis condition:
Chromatographic column: ACQUITY UPLC BEH C18Post (2.1mm × 50mm, 1.7 μm), flow phase: 0.1% formic acid water-first
Alcohol, elution program is shown in Table 3-1-1, flow velocity: 0.3ml/min, column temperature: 50 DEG C, sample size: 5 μ l.
Table 1 gradient elution
Using electro-spray ionization source (ESI), positive ion mode detects, and desolventizing gas is nitrogen, desolventizing temperature:
350 DEG C, flow velocity: 650L/h, ion source temperature: 120 DEG C, use multiple-reaction monitoring (MRM) pattern that medicine ion concentration is carried out
Measuring, 7 kinds of analysis ingredients and interior target optimum MRM parameter are shown in Table 2.
7 compositions and 2 interior target MS parameters in table 2 Yuanhu Zhitong Prescription
Plasma sample pre-treatment:
Take rat plasma 50 μ l, be sequentially added into 50 μ l methanol, 150 μ l containing the internal standard (warfarin sodium 50ng/mL and hydrochloric acid isopropyls
Piperazine 25ng/mL) methanol solution, vortex concussion 3min, 15000r/min be centrifuged 10min, take supernatant 200 μ l, nitrogen dries up,
Redissolving with 100 μ l 50% methanol, vortex 1min, 15000 are centrifuged 5min, take supernatant 5 μ l sample introduction, carry out LC-MS analysis.
The analysis in vivo checking carrying out the present invention includes:
(1) specificity of method is investigated:
The blank plasma of 6 Different Individual and standard are added blood plasma, and (α-allocryptopine and N-1 are 0.5ng/
Ml, tetrahydropalmatine and corydaline are 1ng/ml, and byak-angelicin, imperatorin and isoimperatorin are 2ng/ml), in being not added with
Outside mark, other carry out UPLC-MS/MS analysis by after the method operation under " plasma sample pre-treatment " item, the most different blank blood
Slurry and standard add the chromatogram of blood plasma, to investigate whether the endogenous component in blank plasma exists interference.
(2) range of linearity and lower limit of quantitation (LLOQ):
Methodology confirmation three days in every day prepare 3 set standard curves, with testing concentration as abscissa, determinand with
The peak area ratio of internal standard substance is vertical coordinate, with weighting (W=1/x2) method of least square carries out regressing calculation, tries to achieve linear regression
Equation is standard curve.
Standard curve minimum point concentration 6 samples of preparation were analyzed in the 3rd day in method confirmation, and according to the same day
Standard curve calculates each sample and measures concentration, and LLOQ is the least concentration point on standard curve, and its response value should be blank raw
More than 5 times (S/N >=5) of thing matrix interference thing response value, and precision is expressed as relative standard deviation (relative
Standard deviation, RSD) answer≤20%, accuracy is expressed as bias (bias), should be in the range of ± 20%.
(3) precision and accuracy:
Take blank rat plasma 50 μ L, grasp by " plasma sample standard curve and the preparation of Quality Control (QC) sample " Xiang Tongfa
Make, prepare high, medium and low three concentration (α-allocryptopine and N-1 be 1,100,200ng/ml, tetrahydropalmatine is with purple
Violet alkali is 2,200,400ng/ml, byak-angelicin, imperatorin and isoimperatorin be 4,400,800ng/ml) Quality Control sample
Product, each concentration carries out 6 sample analyses, METHOD FOR CONTINUOUS DETERMINATION three days, calculate recording of quality-control sample according to standard curve on the same day every day
Concentration.According to quality-control sample measurement result calculate this law in a few days, day to day precision and accuracy.
(4) extraction recovery and matrix effect:
Investigate component to be measured impact of matrix effect under variable concentrations, and the blood plasma extraction recovery under the conditions of this.
The standard preparing component to be measured adds plasma sample (basic, normal, high QC concentration, same " plasma sample standard curve and Quality Control (QC) sample
The preparation of product " operation of method under item), after operating, measure concentration (set 3 sample) according to " plasma sample pre-treatment " method;Will
After blank plasma albumen precipitation, standard adds compound mensuration concentration to be measured (set 2 sample);By flowing preparation respective concentration mutually not
Pure sample solution containing substrate measures concentration (set 1 sample).The value of calculation of matrix effect is set 2 sample and set 1 sample
Chromatographic peak area ratio;The value of calculation of extraction recovery is the chromatographic peak area ratio of set 3 sample and set 2 sample.Examine simultaneously
Examine internal standard warfarin sodium (50ng/mL) and the matrix effect of promethazine hydrochloride (25ng/mL) and extraction recovery.
(5) sample stability:
During Method validation, the stability analyzing sample is investigated, including 1 time, steady after 3 freeze-thaw cycle
Qualitative, the short-term stability of the lower 25 DEG C of placement 4h of room temperature, preserve the long-time stability of 2 weeks under 20 DEG C of freezing conditions, and process
After plasma sample in automatic sampler (4 DEG C) place 12h stability.During study on the stability, take blank plasma 50 μ L, press
The Quality Control of basic, normal, high three concentration is prepared according to method below " plasma sample standard curve and the preparation of Quality Control (QC) sample " item
(QC) sample, is added in blank plasma by 1:10, and each concentration carries out 3 sample analyses, with measured value compared with indicating concentration, with
Relative deviation (RE) represents.
Analysis in vivo the result is as follows:
(1) specificity:
After blank rat plasma, the additional standard solution of blank plasma and rat are administered, plasma sample chromatogram is shown in that Figure 1A is extremely
Fig. 1 C.Component to be measured and interior target retention time are specific as follows: α-allocryptopine is 3.55min, tetrahydropalmatine is
3.54min, N-1 are 3.64min, corydaline is 3.68min, byak-angelicin is 4.63min, imperatorin is
5.76min and isoimperatorin are 6.12min, and N-1 is 6.85min, and warfarin sodium (IS) is 4.49min, and hydrochloric acid is different
Promazine (IS) is 5.67min, and the endogenous component in blank plasma does not interferes measuring.
(2) standard curve and lower limit of quantitation:
Article 3, standard curve all shows good linear relationship, α-allocryptopine and four in the following concentration range investigated
Hydrogen berberine: 0.5-500ng/mL, tetrahydropalmatine and corydaline: 1-1000ng/mL, byak-angelicin, imperatorin and different Europe
Peucedanin: 2-2000ng/mL, each ingredient standard curve correlation coefficient (R2) it is all higher than 0.99.Lower limit of quantitation experimental result shows,
Measuring under concentration, the withinday precision (RSD) of 7 kinds of compositions to be measured is respectively 2.4%, 2.8%, 1.9%, 1.9%, 8.1%,
3.9%, 1.7%, accuracy (RE) is respectively 4.0%, 3.0%, 4.0%, 4.0% ,-9.0% ,-3.0%, 5.0%.To be measured
The equation of linear regression of composition is shown in Table 3.
The equation of linear regression of 37 kinds of compositions of table
(3) precision and accuracy:
As shown in table 4, under high, medium and low three concentration, in a few days with day to day precision (RSD) be respectively 1.0%~
5.3% and 1.5%~6.1%, in a few days it is respectively-3.2%~7.1% and-7.0%~7.5% with accuracy in the daytime (RE), number
According to showing that the component to be measured preci-sion and accuracy in rat plasma all meets the analysis requirement of biological sample.
Before table 4 α-allocryptopine, tetrahydropalmatine, N-1, corydaline, byak-angelicin, imperatorin and different Europe
Hu Su preci-sion and accuracy (n=6) in rat plasma
(4) response rate and matrix effect:
Table 5 lists component to be measured and internal standard (the warfarin sodium 50ng/mL of basic, normal, high 3 concentration;Promethazine hydrochloride
Matrix effect and extraction recovery 25ng/mL) investigate result.Extraction recovery result shows, at this blood plasma pre-treating method
Under, precipitation of protein to the extraction recovery of 7 compositions to be measured all more than 88.8%.Matrix effect is investigated result and is shown, this
Under method condition determination, ion suppression or the potentiation of the endogenous material in blood plasma are negligible, to 7 kinds of compositions to be measured
Mass spectrum response not impact.
Before table 5 α-allocryptopine, tetrahydropalmatine, N-1, corydaline, byak-angelicin, imperatorin and different Europe
Hu Su extraction recovery in rat plasma and matrix effect (n=6)
(5) stability:
Before table 6 α-allocryptopine, tetrahydropalmatine, N-1, corydaline, byak-angelicin, imperatorin and different Europe
Hu Su stability (n=6) in rat plasma
Study on the stability result show 7 kinds of component blood slurry samples through three freeze-thaw cycle (RE:-10.4%-10.9%),
Lower 25 DEG C of room temperature places 4h (RE:-5.5%-13.0%), preserves 2 weeks (RE:-10.3%-10.5%) under-20 DEG C of freezing conditions
After the most stable, it is concrete that plasma sample after process in automatic sampler (4 DEG C) places 12h stable (RE:-9.2%-12.1%)
The results are shown in Table 6.
From above table, 7 kinds of compositions all keep stable during storing, processing and measure.
Through checking, this analysis method meets the requirement of Determination of Biological Samples.
It follows that carry out UPLC-MS/MS condition optimizing, the selection of interior target and the optimization of plasma sample pre-treating method.
Primarily look at flowing phase, methanol and acetonitrile relatively good as flowing phase chromatographic peak profile, but acetonitrile is as flowing
Phase time, the response value of byak-angelicin is methanol as 1/10th of flowing phase, so, select methanol as flowing phase.In matter
In analysis of spectrum, flowing mutually adds the acid ingredients such as formic acid, chromatographic peak profile can be significantly improved.Investigate formic acid herein at water
Addition in mutually, finds along with formic acid addition increases, from 0.05%, 0.1% and 0.2%, but the sound of alkaloids composition
Should be obviously enhanced, and its peak shape also makes moderate progress, therefore we have selected a suitable formic acid concn (0.1%) and take into account
Chromatographic peak profile and mass spectrum response to all components to be measured.
When biological sample is analyzed, issuable when being marked with correcting sample pretreatment in being usually added into and analyze
Error, and facilitate sample pretreatment, improve processing speed.For the instrument using this highly sensitive low stability of mass spectrum as inspection
Surveying device, interior target adds especially necessary.In view of we analyzed for coumarin and alkaloid two compounds, first pass through
Analyze similarity computed in software candidate compound and the structural similarity of testing compound, the chemical combination that a large amount of screening structures are similar
Thing, screens candidate compound further by Determination of oil-water partition coefficient, and every element of the first species selects 3 candidate compounds as internal standard,
Then according to chromatograph and mass spectrographic testing result, selecting optimal internal standard, finally we have selected warfarin sodium (for coumarin
Constituents) and two medicines of promethazine hydrochloride (for alkaloid constituents) as the internal standard of this two constituents, respectively it is carried out
Correction.
In test, we attempt comparing albumen precipitation and (include methanol extraction, acetonitrile precipitation and methanol: acetonitrile=1:1
Precipitation), liquid-liquid extraction and Solid-Phase Extraction.In albumen precipitation, the response rate of methanol extraction method is higher than acetonitrile precipitation and methanol:
Acetonitrile=1:1 precipitation, and matrix effect is smaller;Liquid-liquid extraction has been investigated ethyl acetate respectively and has been added 12.5% ammonia and 0.2M
NaOH, the response rate adding 12.5% ammonia is higher than addition 0.2M NaOH, owing to liquid-liquid extraction adds the method matrix effect of alkali
Bigger, and the response rate of albumen precipitation method is higher than liquid-liquid extraction, it is contemplated that the substantial amounts of sample of subsequent experimental, SPE expense
High and relatively take, therefore, this experiment have finally chosen the pre-treating method of methanol extraction albumen.Have found that the organic facies in sample
Ratio, higher than the organic facies ratio in flowing mutually, takes two kinds of methods: one is to redissolve with 50% methanol after supernatant nitrogen dries up,
Two is that supernatant dilutes with equal-volume water.Find that supernatant nitrogen dries up be better than supernatant with water-reducible method through investigating,
Mass spectrum response value after we have also investigated the methanol extraction plasma protein of 3,4,5 times of volumes simultaneously, finds the methanol of 3 times of volumes
Process, component to be measured can be extracted and dilute less more completely, thus obtain the mass spectrum response of maximum.
Therefore, establish in the present invention simple, sensitive and accurately LC-ESI-MS analyze method, for simultaneously
α-allocryptopine in quantitative determination rat plasma, tetrahydropalmatine, N-1, corydaline, byak-angelicin, imperatorin
And isoimperatorin.Sample pre-treatments uses protein precipitation method, simple and fast.This method specificity is good, highly sensitive, and it is fixed
Amount lower limit is respectively 0.5ng/mL (corydaline and tetrahydropalmatine), 1ng/mL (N-1 and α-allocryptopine) and 2ng/
ML (byak-angelicin, imperatorin and isoimperatorin), provides reliable analysis method for follow-up pharmacokinetic.
Hereinafter, 7 main active of Yuanhu Zhitong Prescription pharmacokinetics in rat plasma is studied.
In order to compare the pharmacokinetics of main active after Oral Administration in Rats is administered by single medicinal material and Yuanhu Zhitong Prescription it is
No changing, we are by Rhizoma Corydalis extract, Radix Angelicae Dahuricae extract and corydalis tuber analgesic formula extraction (Rhizoma Corydalis: the Radix Angelicae Dahuricae=2:1)
Respectively to rat oral gavage, compared by the pharmacokinetics behavior of single medicinal material and Yuanhu Zhitong Prescription, thus it is speculated that after both drug combinations
Interaction trend, provide rational basis and guidance for the application of Yuanhu Zhitong Prescription compatibility.
Take angelica root 1kg, pulverize No. 6 sieves.Soaking 1h, with 4 times amount 70% alcohol reflux, extraction time is
2h, extracts 2 times successively, merges filtrate, and 70 DEG C of drying under reduced pressure are to powder, and extraction ratio is 9.52%;Take corydalis tuber medicinal material 1kg,
Pulverized No. 6 sieves.Soaking 1h, with 4 times amount 70% alcohol reflux, extraction time is 2h, extracts 2 times successively, merges and filters
Liquid, 70 DEG C of drying under reduced pressure are to powder, and extraction ratio is 8.15%.
Measuring Rhizoma Corydalis and the content of main active in Radix Angelicae Dahuricae extract respectively, result shows in Rhizoma Corydalis extract
The content of main active is as follows: α-allocryptopine is 3.20mg/kg, and corydaline is 11.59mg/kg, and tetrahydropalmatine is
4.19mg/kg, N-1 is 1.13mg/kg, and in Radix Angelicae Dahuricae extract, the content of main active is as follows: byak-angelicin is
0.69mg/kg, imperatorin is 3.78mg/kg, and isoimperatorin is 1.90mg/kg.
Take a heparin, every 1g, be placed in the volumetric flask of 100mL, be settled to scale with normal saline, be made into 1%
Heparin solution, prepares 500ml altogether, is placed in 4 DEG C and stores for future use.
Weigh Rhizoma Corydalis extract 6.52g, Radix Angelicae Dahuricae extract 3.81g, Yuanhu Zhitong Prescription (Rhizoma Corydalis extract respectively
6.52g, Radix Angelicae Dahuricae extract 3.81g), the aqueous solution adding 50ml grinds to form suspension solution, for rat oral gavage.Medicinal liquid is before use
Preparation.
18 SD rats, body weight 230 ± 20g, it is randomly divided into 3 groups, often group 6, male and female half and half, 12h fasting before being administered, from
By drinking water, gavage gives corydalis tuber analgesic formula extraction, Radix Angelicae Dahuricae extract and Rhizoma Corydalis extract respectively, feeds to raise after being administered 4h
Material.Before being administered and after administration 0.17,0.33,0.67,1,1.5,2,3,4,6,8,12,24,36,48h takes by orbital venous plexus
Blood is about 0.5mL, anticoagulant heparin, and 3500 × g takes blood plasma after being centrifuged 10min, to be measured in-20 DEG C of preservations.
Use the non-compartment model of DAS2.0 data processing software (quantitative pharmacology Professional Committee of Chinese Pharmacological Society)
Method (statistics moments method) carries out pharmacokinetic parameter Cmax、Tmax、t1/2, the calculating of AUC, MRT, CL/F etc..
After in experiment, female rats is administered orally Rhizoma Corydalis extract, plasma sample drug level is significantly larger than male rat blood medicine
Concentration, causes the concentration of corydaline in indivedual plasma sample beyond the range of linearity of standard curve, to exceed linear for concentration
The plasma sample of scope, redeterminates after being diluted with blank plasma, has investigated the dilution effect of sample, experimental result table
Bright, use blank plasma diluting high-concentration sample post analysis, the response rate, blood drug level are had no significant effect.
After 3 groups of each extracts of SD rat oral gavage, use the method for above-mentioned foundation that each time point blood plasma is analyzed, blood
Concentration-time data is shown in Table 7 to 20, and mean blood plasma concentration-time data is shown in Table 21.Non-compartment model method is used to calculate medicine generation
Kinetic parameter, the results are shown in Table 22 and 23.
Table 7 rat oral gavage gives blood concentration-time data (ng/ml, the n of α-allocryptopine after unit's Rhizoma Corydalis extract
=6)
N.d. do not detect, at below LLOQ
Table 8 rat oral gavage gives the blood concentration-time data (ng/ of α-allocryptopine after corydalis tuber analgesic formula extraction
Ml, n=6)
Table 9 rat oral gavage gives blood concentration-time data (ng/ml, the n=of tetrahydropalmatine after Rhizoma Corydalis extract
6)
N.d. do not detect, at below LLOQ
Blood concentration-time data (ng/ml, the n of tetrahydropalmatine after table 10 Oral Administration in Rats corydalis tuber analgesic formula extraction
=6)
Table 11 rat oral gavage gives blood concentration-time data (ng/ml, the n of N-1 after Rhizoma Corydalis extract
=6)
Table 12 rat oral gavage gives the blood concentration-time data (ng/ of N-1 after corydalis tuber analgesic formula extraction
Ml, n=6)
Table 13 rat oral gavage gives the blood concentration-time data (ng/ml, n=6) of corydaline after Rhizoma Corydalis extract
N.d. do not detect, at below LLOQ
Table 14 rat oral gavage gives blood concentration-time data (ng/ml, the n of corydaline after corydalis tuber analgesic formula extraction
=6)
Table 15 rat oral gavage gives the blood concentration-time data (ng/ml, n=6) of byak-angelicin after Radix Angelicae Dahuricae extract
Table 16 rat oral gavage give byak-angelicin after corydalis tuber analgesic formula extraction blood concentration-time data (ng/ml,
N=6)
Table 17 rat oral gavage gives the blood concentration-time data (ng/ml, n=6) of imperatorin after Radix Angelicae Dahuricae extract
Table 18 rat oral gavage give imperatorin after corydalis tuber analgesic formula extraction blood concentration-time data (ng/ml,
N=6)
Table 19 rat oral gavage gives blood concentration-time data (ng/ml, the n=of isoimperatorin after Radix Angelicae Dahuricae extract
6)
Table 20 rat oral gavage gives the blood concentration-time data (ng/ of isoimperatorin after corydalis tuber analgesic formula extraction
Ml, n=6)
Table 21 mean blood plasma concentration-time data
Table 22 Rhizoma Corydalis is alone and main pharmacokinetic parameter (n=6) after Yuanhu Zhitong Prescription oral administration
**P<0.01,*P < 0.05 is for Rhizoma Corydalis
Table 23 Radix Angelicae Dahuricae is alone and main pharmacokinetic parameter (n=6) after Yuanhu Zhitong Prescription oral administration
**P<0.01,*P < 0.05 is for the Radix Angelicae Dahuricae
Pharmacokinetic parameter result of calculation shows: as in figure 2 it is shown, SD rat oral gavage Yuanhu Zhitong Prescription group and Rhizoma Corydalis group
Comparing, the peak time of α-allocryptopine has extended, and internal average residence time extends 0.8 times, has significant difference,
P < 0.01, AUC0→tAnd AUC0→∞Increase, but not there is statistical significance.
As it is shown on figure 3, Yuanhu Zhitong Prescription group is compared with Rhizoma Corydalis group, the AUC of tetrahydropalmatine0→t、AUC0→∞And MRT(0-t)
Having significance to improve, P < 0.01, peak time extends 3.8 times, P < 0.05.
As shown in Figure 4, Yuanhu Zhitong Prescription group is compared with Rhizoma Corydalis group, and N-1 peak concentration improves 2 times, when reaching peak
Between extend 4 times, internal average residence time extends 0.8 times, P < 0.01, AUC0→tAnd AUC0→∞All significantly increase, there is system
Meaning learned by meter.
As it is shown in figure 5, Yuanhu Zhitong Prescription group is compared with Rhizoma Corydalis group, corydaline peak concentration increases, and peak time prolongs
Having grown 2 times, had statistical significance, internal average residence time extends 0.65 times, has statistical significance, P < 0.05.
Fig. 6 to Fig. 8, respectively derives from composition byak-angelicin in the Radix Angelicae Dahuricae, imperatorin, isoimperatorin 3 compositions
Blood concentration-time curve chart.It can be seen that relative to single medicinal material, the AUC of these 3 compositions in compound recipe0→tWith
AUC0→∞All significantly reduce.Meanwhile, chemically from the point of view of compositional classification, angelicin, imperatorin, 3 one-tenth of isoimperatorin adhere to separately
In coumarinoids, different with 4 alkaloids compositions, these 3 composition AUC0→tAnd AUC0→∞All significantly reduce, biological profit
Expenditure reduces, and represents it is not same class composition, the AUC of chemical composition0→tAnd AUC0→∞Change different, same class composition
AUC0→tAnd AUC0→∞Variation tendency has concordance.And, according to document, Coumarins composition has hepatic injury effect, above-mentioned
Result provides foundation for compatibility attenuation.
In Yuanhu Zhitong Prescription, the alkaloid component in Rhizoma Corydalis is the main component of analgesic activity, the Rhizoma Corydalis compatibility Radix Angelicae Dahuricae,
The Radix Angelicae Dahuricae can extend the peak time of principal alkaloid constituents in Rhizoma Corydalis, keeps the time lengthening of effective blood drug concentration, simultaneously
AUC0→tAnd AUC0→∞Significantly increase, make the blood drug level longer time be in Valid concentration, preferably play drug effect, from
The angle of pharmacokinetics, explains Rhizoma Corydalis and the principle of the Radix Angelicae Dahuricae 5.Meanwhile, we find from experimental result, and the Radix Angelicae Dahuricae is joined
After 5 Rhizoma Corydalis, Rhizoma Corydalis significantly reduces the blood drug level of main coumarinoids in the Radix Angelicae Dahuricae, shows Rhizoma Corydalis and the Radix Angelicae Dahuricae
There is drug-drug interactions in two taste Chinese medicines, the physiological disposition research for Yuanhu Zhitong Prescription is laid a good foundation.
It follows that calculate and the AUC-time graph of 7 main components of matching.
The AUC-time graph of 7 compositions in Yuanhu Zhitong Prescription is calculated according to following trapezoidal method computing formula:
Wherein, t0=0, A (0)=0, C (0)=0.
Following table can be obtained by above-mentioned formula:
Table 24 medicine AUC-time data
7 main components relatedness between the change of AUC-time graph and the compound structure of single medicinal material and compound recipe is divided
Analysis:
MedChem Studio software, as a visualization Chemoinformatics research platform, with Tanimoto coefficient, right
7 compounds carry out structural similarity evaluation.Compound similarity score between any two is shown in Table 23. and utilizes SPSS software, logical
Crossing cluster analysis (PCA) to be analyzed chemical constitution similarity score between any two, result is shown in Fig. 9.
As can be seen from the results, α-not recessive alkali, corydaline, tetrahydropalmatine and N-1 belong to alkaloids
Compound, carries out cluster analysis result with structural similarity marking and shows, from being divided into same class;Imperatorin, different Imperatoria ostruthium
Element and byak-angelicin belong to coumarin kind compound, carry out cluster analysis result with structural similarity marking and show, from being divided into
Another kind of.
25 7 compositions of table chemical constitution similarity score between any two
7 main components are as follows at the AUC-time changing curve calculating function of single medicinal material and compound recipe:
Wherein, AUCviAUC for composition I between different time points, single medicinal material and compound recipe changes;AUCdiFor in difference
The AUC of the single medicinal material of time point;AUCfiThe AUC of the compound recipe of different time points, CmaxFor maximum dense between single medicinal material and compound recipe
Degree.
In Yuanhu Zhitong Prescription and single medicinal material, 7 composition AUC-time changing curves are shown in Figure 10, it can be seen that along with
The prolongation of time, Coumarins composition (imperatorin, isoimperatorin and byak-angelicin) AUCviConstantly increase, but, biological
Alkali components (α-not recessive alkali, corydaline, tetrahydropalmatine and N-1) AUCviConstantly reduce.Further to change song
Line carries out cluster analysis, and result shows, 3 Coumarins compositions (imperatorin, isoimperatorin and byak-angelicin) are gathered
Same class, 4 alkaloids compositions (α-not recessive alkali, corydaline, tetrahydropalmatine and N-1), chemical constitution is described
Similar composition, has similar AUCviChange curve.
Being analyzed chemical constitution similarity score between any two by cluster analysis, result is shown in Figure 11.
It follows that utilize 1 compound to predict other chemical combination at the AUC-time graph Changing Pattern of single medicinal material and compound recipe
Thing is AUC-time graph in compound recipe.
By calculating the ratio of each composition AUC sum in Yuanhu Zhitong Prescription with Rhizoma Corydalis (or Radix Angelicae Dahuricae) and its meansigma methods
7 kinds of compositions can be divided into two classes by discovery, and thus propose a kind of new Forecasting Methodology.
First, the ratio Γ of each composition AUC sum in compound recipe and single medicinal material and its meansigma methods is calculated+, this ratio
Γ+Computing formula as follows:
Wherein, x (ti) be in compound recipe composition I at the AUC in i moment, b (ti) for become I in single medicinal material in the i moment
AUC。
Each composition is at the ratio Γ in each moment+It is shown in Table 24.
The each composition of table 26 is at the ratio Γ in each moment+
Scatterplot as shown in figure 12 is made according to upper table.
As seen from Figure 12, by degree of closeness, above-mentioned seven curves can be divided into two classes, i.e. α-not recessive alkali, Rhizoma Corydalis
B prime-S, N-1-S and corydaline are a class, and byak-angelicin, imperatorin and isoimperatorin-S are another kind of.
Following table is tetrahydropalmatine-S, before N-1-S, corydaline and α-recessive alkali and imperatorin, different Europe
Hu Su-S Γ corresponding to byak-angelicin+Ratio between value.
Before table 27 tetrahydropalmatine-S, N-1-S, corydaline and α-recessive alkali and imperatorin, different Europe
Hu Su-S Γ corresponding to byak-angelicin+Ratio between value
By upper table it can be seen that after 3 hours corresponding Γ+Ratio between value be all distributed in interval (0.84,
1.11 in).
Speculating based on above-mentioned theory, we can use following method at known composition A at the Γ in each moment+ValueComposition B AUC in single medicinal material (compound recipe)And in compound recipe (single medicinal material) the 3rd hour
AUC x (t7In the case of), it was predicted that composition B is 4 hours and later AUC in compound recipe (single medicinal material)
Below, for sake of convenience, brief noteI=0,1,2 ...,
n-1.Linear equation group as follows can be obtained by (1) (3).
Solve this equation group, can obtain and solve as follows:
That is
Embodiment 1 is by the Γ of composition α-not recessive alkali+Value prediction composition tetrahydropalmatine-S in Yuanhu Zhitong Prescription 4 hours
After AUC
Now composition α-not recessive alkali is corresponding to moment tiΓ+Value a (ti) and tetrahydropalmatine-S right in Rhizoma Corydalis
Should be in moment tiAUC b (ti) (i=7,8 ..., 13) such as following table.
The Γ of table 28 α-not recessive alkali+Value a (ti) and tetrahydropalmatine-S AUC in Rhizoma Corydalis
Additionally x (t7)=971.4730917.Finally tetrahydropalmatine-S is obtained in Yuanhu Zhitong Prescription according to (10) (n=14)
Corresponding to moment tiAUC x (ti) (i=8,9 ..., 13).Now correlated results is listed in the table below.
Table 29 tetrahydropalmatine-S AUC experiment value in Yuanhu Zhitong Prescription and predictive value comparable situation
Embodiment 2 is by the Γ of composition α-not recessive alkali+Value prediction composition N-1-S in Yuanhu Zhitong Prescription 4 hours
After AUC
According to method as above, following result can be obtained:
Table 30 N-1-S AUC experiment value in Yuanhu Zhitong Prescription and predictive value comparable situation
Embodiment 3 is by the Γ of composition α-not recessive alkali+Value prediction composition corydaline is in Yuanhu Zhitong Prescription after 4 hours
AUC
According to method as above, following result can be obtained:
Table 31 corydaline AUC experiment value in Yuanhu Zhitong Prescription and predictive value comparable situation
Embodiment 4 is by the Γ of composition byak-angelicin+Value prediction composition imperatorin is in Yuanhu Zhitong Prescription after 4 hours
AUC
According to method as above, following result can be obtained:
Table 32 imperatorin AUC experiment value in Yuanhu Zhitong Prescription and predictive value comparable situation
Embodiment 5 is by the Γ of composition byak-angelicin+Value prediction composition isoimperatorin-S is in Yuanhu Zhitong Prescription after 4 hours
AUC
According to method as above, following result can be obtained:
Table 33 imperatorin AUC experiment value in Yuanhu Zhitong Prescription and predictive value comparable situation
Claims (5)
1. Chinese medicines is for dynamic (dynamical) curve simulation and a Forecasting Methodology, and it is after the complex system of oral Chinese medicine prescription, sends out
Now similar with confirming chemical constitution composition has similar change of pharmacokinetics, thus by principal component in each moment
Pharmacokinetic parameter predicts that the pharmacokinetic parameter of other structure analogous components, described method include:
Step 1. obtains its blood concentration-time curve in single medicinal material and compound medicines respectively to composition A;
Step 2. calculating composition A is each blood concentration-time area under a curve measuring the moment in single medicinal material and compound medicines
AUC, and then obtain its AUC-time changing curve;
Step 3. calculating composition A is the AUC sum in each moment and the ratio Γ of meansigma methods in single medicinal material and compound medicines+, it calculates public affairs
Formula is as follows:
Wherein, xA(ti) be composition A in the compound medicines AUC in i-th moment, yA(ti) it is composition A i-th moment in single medicinal material
AUC;
Composition B is done the cluster analysis of chemically based structural similarity by step 4.;
If step 5. belongs to a class together according to cluster analysis result composition B and composition A, then can be at known composition A at the Γ in each moment+
Value, composition B AUC in single medicinal material or compound medicines and the situation of the AUC of the 3rd hour in compound medicines or single medicinal material thereof
Under, it was predicted that composition B is the 4th hour and later AUC-time graph in compound medicines or single medicinal material, wherein the 3rd hour i.e. t7Time
Carve, the 4th hour i.e. t8Moment, that is
Or
Wherein, xB(ti) be composition B in the compound medicines AUC in i-th moment, yB(ti) it is composition B i-th moment in single medicinal material
AUC.
Chinese medicines the most according to claim 1 is for dynamic (dynamical) curve simulation and Forecasting Methodology, logical in wherein said step 1
Cross high performance liquid chromatography mass spectrum/mass spectrometry to obtain the blood concentration-time curve of composition A in single medicinal material and compound medicines.
Chinese medicines the most according to claim 2, for dynamic (dynamical) curve simulation and Forecasting Methodology, wherein selects formic acid water-first
Alcohol is as flowing phase, and uses electro-spray ionization source ESI, and positive ion mode detects, and many reaction detection MRM pattern pair
Medicine ion concentration is measured.
The most according to claim 2, Chinese medicines is for dynamic (dynamical) curve simulation and Forecasting Methodology, wherein adopts in sample pre-treatments
Use protein precipitation method.
Chinese medicines the most according to claim 1 is for dynamic (dynamical) curve simulation and Forecasting Methodology, logical in wherein said step 2
Cross trapezoidal method to calculate in single medicinal material and compound medicines composition A at the lower area of blood concentration-time curve of each time point, described
Trapezoidal method computing formula is as follows:
Wherein, A (ti) be in compound recipe and single medicinal material composition A at the AUC in the i-th moment, C (ti) it is composition A in compound recipe and single medicinal material
At the blood drug level in the i-th moment, and t0=0, A (0)=0, C (0)=0.
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