objective （BiopharmaceuticalsClassification System，BCS）.
method Using experimental and computer prediction softwarePipeline Pilot 8.5、ChemDrawThe solubility and permeability of Periplocoside, Periplocoside and periplocybin were studied, and according to the experimental and predicted valuesBCSClassification method for3Who are classified.
result According to the experimental results, periplocatin, periplocatin and periplocatin wereBCS IIIClass of drugs, which is different from the classification results predicted by different software. base onClgPThe results of permeability are consistent with the experimental results; base onlgCsBased on the solubility ofAlgP、lgDThe predicted results of permeability are contrary to the experimental results.
conclusion Periplocatin, periplocatin and periplocatin wereBCS IIIClass drugs,3Their solubility decreased in turn, but they still belonged to high solubility components.3The permeability is the key factor affecting its absorption. There is a great difference between the predicted value of biopharmaceutical properties of the active ingredients of A-type cardiac glycosides based on chemical structure and the experimental results. The oral absorption of traditional Chinese medicine preparations containing such ingredients was analyzedBCSIt is suggested to use a variety of methods to correct the data and increase the reliability of the results.
preface
XiangjiapiPeriplocae CortexIt is Periploca fortunei, a plant of AsclepiadaceaePeriploca sepium Bge. The dry root bark has the functions of diuresis, detumescence, dispelling wind and dampness, and strengthening muscles and bones. Clinically, it is mainly used to treat lower limb edema, palpitations, shortness of breath, wind cold dampness, waist and knee soreness and other symptoms[1]Periplocatin is a class of A-type cardiac glycosides in cortex Periplocae[2], with pharmacological effects of cardiotonic diuresis, anti-tumor, anti-inflammatory, immune regulation, etc[3-10]。Periplocatin、PeriplocatinandPeriplocatinLike other A-type cardiac glycosides, it can selectively act on heartdirty[11], which can strengthen positive muscle strength, increase myocardial contractility and slow down heart rate. It is the main pharmacodynamic component of cortex Periplocae. And compared with cardiac glycosides such as digoxigenin and digoxin, its therapeutic window is wider, but excessive use will still lead to clinical medication risks, such as atrioventricular block, premature beats, tachycardia, atrial fibrillation and other cardiac toxicity.
Biopharmaceutical classification system（Biopharmaceuticals Classification System，BCS）Amidonetc.[12]stay1995A scientific framework for classifying drugs according to their water solubility and intestinal permeability was first proposed in. The classification system has received more and more attention since it was proposed, and gradually obtained the approval of the U.S. Food and Drug Administration（Food and Drug Administration，FDA）European Medicines Agency（EuropeanMedicines Agency，EMA）And the World Health Organization（Word Health Organization，WHO）And apply it to the relevant guiding principles.FDAstay2000In, he put forward the proposal of "according toBCSExempt the guiding principles for in vivo bioavailability and bioequivalence studies of immediate release solid oral preparations, and constantly revise them. Eligible related drugs can apply for bioequivalence exemption, suggesting that they have in vitro and in vivo correlation. base onBCSThe bioequivalence exemption greatly simplifies the time and economic cost of research and development of a large number of generic drugs while ensuring the quality of drugs. At present, for traditional Chinese MedicineBCSClassification studies are mostly the evaluation of single component biopharmaceutical attributes.
Solubility and permeability areBCSOf the classification system2The three core elements are the basic parameters that affect the degree and speed of drug absorption in vivo. At present, there are many methods for the determination of solubility and permeability. This experiment usesFDAThe solubility and permeability of Periplocoside, Periplocoside and periplocybin were studied by the recommended equilibrium solubility method and in vitro animal experiments; At the same time2Compound parameter prediction softwarePipelinePilot 8.5andChemDrawforecast3Solubility parameterslgCsPermeability parametersAlgP、pHDependence distribution coefficientlgDas well asClgPValues. BCSClassification method for3The authors studied the classification system of Biopharmaceutics, and discussed the reasons for the differences between experimental values and predicted values, providing reference ideas and technical support for the research and development of new botanical drugs, reducing the cost and time of new drug research and development, and accelerating the research and development process of new natural drugs.
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discuss
3.1 Reasons for differences between experimental and predicted values
Shake flask method was used in this experiment-UPLCThe equilibrium solubility of drugs was determined by HPLC. [23].Pipeline Pilot 8.5The simulation software predicts the solubility of compounds based on the electrical topological state index, which is determined by the electronic properties of atoms and the topological environment of each backbone atom in the molecule. Compared with the experiment, it has a certain error, so the solubility of Periplocoside, Periplocoside and periplocybin is subject to the experimental results.Pipeline Pilot 8.5Prediction of compounds by simulation softwareAlgP、lgDIt is based on the atom group contribution method, and the predicted value is obtained from the hydrophobic constants of the added atoms and groups, which is determined by the compound structure. .
The difference between the measured and predicted values of the solubility of Periplocoside, Periplocoside and periplocybin may be related to the cognition of the prediction software on the structure of steroidal mother nucleus. Steroidal parent nucleus is a kind of parent nucleus with cyclopentane polyphenyl structure. Its basic skeleton is a carbon frame, with small polarity and poor solubility, which may be predicted by the software3The reason for the low solubility of the components. Caco-2Cells and high permeability in the intestinal perfusion model in vivo. P-gpandP450Involvement of enzymes[17]However, there is no exact study on its transport mode and mechanism. The existing calculation methods have great differences in the calculation of ionizable ionic components, and the results obtained by different absorption experimental methods are different. It is further explained that there must be many different ways of its absorption mechanism. If we want to accurately classify it, it is still necessary to correct each other with multiple experimental methods and multiple prediction methods.
3.2 Periplocatin、Periplocatin、Periplocatin3Solubility、Permeability、Toxicity Comparison
The solubility of cardiac glycosides is related to the number and type of sugars contained in the molecule, the hydroxyl number and position of aglycones[24]. according to this experiment3The order of their solubility is Periplocoside > Periplocoside > periplocybin, which is presumed to be the structural reason. Periplocin contains2Sugar groups, with the largest polarity and the best solubility. The solubility of periplocybin is higher than that of periplocybin because periplocybin has more Canadian sesame sugar than periplocybin.
According to this experiment, the permeability of periplocatin was higher than that of periplocatin, and periplocatin did not permeate in the small intestine. The possible reasons wereKrebs- Ringer’s. It has been reported that Periplocoside is converted into Periplocoside after deglycosylation, and the latter has increased lipid solubility and permeability[25]。
Periplocatin is a toxic and effective component of cortex Periplocae.Bloiseetc.[26]take3Human myeloid leukemiaU937Cells andAndrogen independent prostate cancerPC3It was found that the inhibition rate of Periplocoside was the highest, followed by Periplocoside and periplocybin, suggesting that its toxicity might be Periplocoside > periplocybin > periplocybin.
3.3 Periplocin and digoxin
Digoxin and digoxigenin, which belong to cardiac glycosides and have similar chemical structure, also have the same hydrolysis process. Digoxigenin digoxigenin digoxigenin digoxigenin, digoxigenin monodigoxigenin and digoxigenin can be successively produced by hydrolysis and deglycosylation of digoxigenin. Digoxigenin can be hydrolyzed and deglycosylated to produce digoxigenin digoxigenin, digoxigenin monodigoxigenin and digoxigenin in turn[27]The chemical structure of a drug determines its physicochemical properties and then directly affects the metabolic process of drug molecules in the body. The chemical structure of digoxin is very similar to that of digoxigenin, which is only higher than that of digoxigenin in the steroidal nucleusC-12More carbon atoms1Hydroxyl groups, whereby2Although they are different in absorption, distribution, metabolism and excretion, they still have many similarities. For example,2All areP-gpbottom matter[28-30], mainly distributed in heart, liver, spleen, skeletal muscle, etc[31]The metabolic modes include deglycosylation and hydrogenation of lactone rings[31-32]Therefore, the metabolic mode of digoxin can provide references for the metabolic process of Periplocoside, Periplocoside and periplocybin in vivo.
References (omitted)
Come Source: Xing Xue, Guo Xiao Xiao, renxiaoliang, Zhou Liwei, Wang Taiyi, Liu Hong, Wang Cute Study on the classification of Periplocoside, Periplocoside and periplocybin biopharmaceuticals [j].the main contents of this paper are as follows:the Biological Pharmaceutics of Periplocoside, periplocybin and periplocybin in periplocybin and periplocybin in periplocybin
Chinese herbal medicine, 2019, 50 (5): 1082-1087