CN105769998A - Application of Danhong injection as uptake type transporter OATP inhibitor - Google Patents
Application of Danhong injection as uptake type transporter OATP inhibitor Download PDFInfo
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- CN105769998A CN105769998A CN201610237620.6A CN201610237620A CN105769998A CN 105769998 A CN105769998 A CN 105769998A CN 201610237620 A CN201610237620 A CN 201610237620A CN 105769998 A CN105769998 A CN 105769998A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/53—Lamiaceae or Labiatae (Mint family), e.g. thyme, rosemary or lavender
- A61K36/537—Salvia (sage)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
- A61K36/286—Carthamus (distaff thistle)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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Abstract
The invention relates to application of Danhong injection as an uptake type transporter OATP inhibitor.According to the application, a human liver cell model cultured in an in-vitro sandwich mode and a 293 cell strain stably transinfected with the most important OATP1B1, OATP1B3 and OATP2B1 genes in the human OATP transporter family are adopted to inspect the effect of Danhong injection on OATP at the cell level.It is found through results that Danhong injection has a certain inhibiting effect on all the three types of uptake type OATP transporters; in a stably-transinfected cell strain model, the half-inhibitory concentration (IC50) obtained in testing with a standard control substrate is 0.1-0.2% (mL:mL), and the half-inhibitory concentration obtained when rosuvastatin serves as a substrate is 0.14-0.72%; in the human liver cell model, Danhong injection also has an inhibiting effect on liver cell uptake of rosuvastatin with OATP as a main uptake way, and the half-inhibitory concentration (IC50) is 0.85% (mL:mL).
Description
Technical field
The present invention relates to the application as picked-up type transporter OATP inhibitor of a kind of DANHONG ZHUSHEYE, particularly relate to the application as picked-up type transporter OATP1B1, OATP2B1 and OATP1B3 inhibitor of a kind of DANHONG ZHUSHEYE.
Background technology
OATP (organicaniontransportproteins), i.e. organic anion transporter, for the most important picked-up type transporter (i.e. absorption type transporter) having now been found that, multiple vitals there is expression, as intestinal epithelial cell, hepatocyte, blood brain barrier endotheliocyte etc., be directly connected to multi-medicament, nutrient substance, the absorption of endogenous material, internal transhipment and distribution and the vivo biodistribution based on the material of liver elimination and convert.
Research at present learns there are 11 members in OATP superfamily, and OATP1B1 sets forth maximum medicine absorption type transporters at present.OATP1B1 is high expressed outside hepatocellular basement membrane, it is possible to absorb from the both sexes endogenous material in hepatic portal vein source, xenobiotics and multi-medicament, the conventional clinical medicine such as including lipid-lowering statins.
OATP1B3 is liver specificity transporter, is distributed in usual limitation on the liver plasma membrane of hepatocyte sinusoid side, recent studies have found that, there is also high expressed in the tumor tissues such as carcinoma of prostate, colon cancer, pulmonary carcinoma and cell.In addition, OATP1B3 can pass through to act on Pregnane X Receptor (pregnaneXreceptor, and composition androstane receptor (constitutiveandrostanereceptor PXR), the transhipment of nuclear receptor ligands such as CAR), affect the transcriptional activity of internal PXR and CAR, thus regulating medicine metabolic enzyme, such as the expression of Cytochrome P450 3A4 (CYP3A4).
OATP2B1 is then widely distributed in the positions such as human liver, small intestinal, brain, the heart, kidney, Placenta Hominis and platelet; and energy some compound of specific transhipment; including endogenous material such as sulfobromophthalein sodium, 3-OES, dehydroepiandrosterone sulfate, taurocholate etc. and multi-medicament; such as Fexofenadine, glibenclamide and statins, there is very important effect.
It has recently found that, OATP family various transporter albumen mostly is high anomaly, all relevant with ethnic group, disease, ecological environment, therefore for new drug development, pathomechanism research and to evade the toxic and side effects that drug drug interaction causes all significant in the effect of drugs and OATP.The transport of drug of OATP1B1 and OATP1B3 mediation and interaction have been listed in U.S. FDA/EMA/ China of the European Union CFDA guideline to the required research project of new drug, and the importance of OATP2B1 research also deploys positive discussion in the industry.At present, the hepatocyte model that common method is original cuiture of medicine and OATP effect and stable cell strain model.
DANHONG ZHUSHEYE, a kind of ejection preparation being widely used in cardiovascular and cerebrovascular disease, be mainly composed of Radix Salviae Miltiorrhizae, Flos Carthami and water for injection, clinically and have multiple studies have shown that DANHONG ZHUSHEYE associating lipid-lowering statins (mostly being the substrate of OATP1B1 and OATP1B3) can obviously reduce the blood fat of functions in patients with unstable angina, hs-CRP, FIB level.But at present to DANHONG ZHUSHEYE at drug interaction with to the research in transporter effect, it is still blank out.
Summary of the invention
The technical problem to be solved is to provide the application as picked-up type transporter OATP inhibitor of a kind of DANHONG ZHUSHEYE, and DANHONG ZHUSHEYE can be used for treating the disease relating to OATP transporter inhibitors.
This invention address that the technical scheme that above-mentioned technical problem adopts is: a kind of DANHONG ZHUSHEYE is as the application of picked-up type transporter OATP inhibitor.
Wherein, described picked-up type transporter OATP is one or more in OATP1B1, OATP2B1 and OATP1B3.
Wherein, the manufacturer of described DANHONG ZHUSHEYE is Heze Buchang Pharma Co., Ltd., and product batch number is 13082026, and the quasi-word of traditional Chinese medicines is Z20026866.
Wherein, the action mode of described DANHONG ZHUSHEYE is: described DANHONG ZHUSHEYE volume fraction≤2% in hatching solution, for instance 1.9%, 1.8%, 1.7%, 1.6%, 1.5%, 1.4%, 1.3%, 1.2%, 1.1%, 1.0%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05% or 0.02%.
Compared with prior art, it is an advantage of the current invention that: all transporters in picked-up type transporter OATP family are had certain inhibitory action by DANHONG ZHUSHEYE, especially that the inhibitory action of three kinds of most important transporters (OATP1B1, OATP1B3 and OATP2B1) is higher.
When with standard endogenous material 3-OES (Estrone3-sulfatepotassium (No. CAS: 1240-04-6)) and 17 beta estradiol 3-(β-maltonic acid sodium) (β-Estradiol3-(β-D-glucuronide) sodium (No. CAS: 14982-12-8)) for substrate, having high inhibition effect, half suppression ratio IC50 in stable cell strain model is 0.1～0.2% (mL:mL)；When with Rosuvastatin for substrate, in stable cell strain model, half suppression ratio IC50 is 0.14～0.72% (mL:mL)；Simultaneously on human liver cell model, integrated survey DANHONG ZHUSHEYE also has inhibitory action to the hepatocyte picked-up that OATP is the Rosuvastatin mainly absorbing approach, and half suppression ratio IC50 is at 0.85% (mL:mL).
Therefore, DANHONG ZHUSHEYE is a kind of novel OATP inhibitor；And based on DANHONG ZHUSHEYE extensive use clinically with without the feature of absorption loss, new clinical indication not only can be increased, it is possible to for avoiding the drug interaction between drug combination to provide theoretical foundation.
Again because picked-up type transporter OATP is had certain inhibitory action by DANHONG ZHUSHEYE, DANHONG ZHUSHEYE can be used for treating the disease relating to OATP transporter inhibitors.
Accompanying drawing explanation
Fig. 1 be with sandwich cultivate human liver cell for study model, with Rosuvastatin for substrate, the DANHONG ZHUSHEYE inhibitory action schematic diagram to hOATP；
Fig. 2 is with OATP1B1-293 cell for study model, with 17 beta estradiol 3-(β-maltonic acid sodium) for substrate, and the DANHONG ZHUSHEYE inhibitory action schematic diagram to hOATP1B1；
Fig. 3 is with OATP1B3-293 cell for study model, with 17 beta estradiol 3-(β-maltonic acid sodium) for substrate, and the DANHONG ZHUSHEYE inhibitory action schematic diagram to hOATP1B3；
Fig. 4 is with OATP2B1-293 cell for study model, with 3-OES for substrate, and the DANHONG ZHUSHEYE inhibitory action schematic diagram to hOATP2B1；
Fig. 5 is with OATP1B1-293 cell for study model, with Rosuvastatin for substrate, and the DANHONG ZHUSHEYE inhibitory action schematic diagram to hOATP1B1；
Fig. 6 is with OATP1B3-293 cell for study model, with Rosuvastatin for substrate, and the DANHONG ZHUSHEYE inhibitory action schematic diagram to hOATP1B3；
Fig. 7 is with OATP2B1-293 cell for study model, with Rosuvastatin for substrate, and the DANHONG ZHUSHEYE inhibitory action schematic diagram to hOATP2B1.
Detailed description of the invention
Below in conjunction with accompanying drawing embodiment, the present invention is described in further detail.
The picked-up transporter OATP inhibitor of the present embodiment is specially DANHONG ZHUSHEYE, DANHONG ZHUSHEYE be mainly composed of Radix Salviae Miltiorrhizae, Flos Carthami and water for injection.
The manufacturer of the DANHONG ZHUSHEYE that the present embodiment specifically adopts is Heze Buchang Pharma Co., Ltd., and product batch number is 13082026, and the quasi-word of traditional Chinese medicines is Z20026866.
The present embodiment adopts the human liver cell model of external sandwich cultivation and 293 cell strains of stable transfection people OATP1B1, OATP1B3 and OATP2B1 gene, investigates the DANHONG ZHUSHEYE inhibitory action to OATP from cellular level.Specifically utilize 293 cell strains of human liver cell model that sandwich cultivates and stable transfection people's OATP gene, adopt multiple specific substrate, such as endogenous material 3-OES, 17 beta estradiol 3-(β-maltonic acid sodium) (EST) and exogenous drugs Rosuvastatin, to prove that DANHONG ZHUSHEYE is inhibited to picked-up type transporter OATP, test result is in Table 1 and table 2；Fig. 1～7 respectively illustrate the DANHONG ZHUSHEYE of the variable concentrations inhibitory action to different OATP transporters simultaneously.
The hepatocyte of Rosuvastatin is absorbed and suppresses by table 1. DANHONG ZHUSHEYE
The table 2. DANHONG ZHUSHEYE half-inhibition concentration (IC to picked-up transporter OATP50) value
From table 1 it is apparent that people OATP1B1, OATP1B3 and OATP2B1 transporter are had obvious inhibitory action by DANHONG ZHUSHEYE.When with standard endogenous material (3-OES and 17 beta estradiol 3-(β-maltonic acid sodium)) for substrate, stable cell strain model has high inhibition effect, half suppression ratio IC50It is 0.1～0.2% (mL:mL).When with Rosuvastatin for substrate, half suppression ratio IC in stable cell strain model50Being 0.14～0.72% (mL:mL), in human liver cell model, half-inhibition concentration is 0.85%.
Comprehensive data above, in testing with the picked-up of external human liver cell model and 293 cell strains of stable transfection people's OATP gene, liver transporter OATP1B1, OATP1B3 and OATP2B1 are had high inhibition effect by DANHONG ZHUSHEYE, half-inhibition concentration numerical value is below 1%, and the experimental result of two kinds of cell models have also been obtained and is mutually authenticated.Therefore, DANHONG ZHUSHEYE can as the inhibitor of a kind of novel picked-up type transporter OATP.
The concentration of indication of the present invention all refers to each material volume fraction hatching in solution in picked-up experiment or molar concentration, as 2% DANHONG ZHUSHEYE refers to that DANHONG ZHUSHEYE volume fraction in hatching solution is 2%；Concentration of substrate 1 μM refers to that substrate compounds concentration in hatching solution is 1 μm of ol/L, by that analogy.
Above content is only presently preferred embodiments of the present invention, for those of ordinary skill in the art, according to the thought of the present invention, all will change in specific embodiments and applications, and this specification content should not be construed as limitation of the present invention.
Claims (4)
1. a DANHONG ZHUSHEYE is as the application of picked-up type transporter OATP inhibitor.
2. apply as claimed in claim 1, it is characterised in that: described picked-up type transporter OATP is one or more in OATP1B1, OATP2B1 and OATP1B3.
3. apply as claimed in claim 1, it is characterised in that: the manufacturer of described DANHONG ZHUSHEYE is Heze Buchang Pharma Co., Ltd., and product batch number is 13082026, and the quasi-word of traditional Chinese medicines is Z20026866.
4. apply as claimed in claim 1, it is characterised in that the action mode of described DANHONG ZHUSHEYE is: described DANHONG ZHUSHEYE volume fraction≤2% in hatching solution.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610237620.6A CN105769998A (en) | 2016-04-14 | 2016-04-14 | Application of Danhong injection as uptake type transporter OATP inhibitor |
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| CN201610237620.6A CN105769998A (en) | 2016-04-14 | 2016-04-14 | Application of Danhong injection as uptake type transporter OATP inhibitor |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109381468A (en) * | 2018-10-29 | 2019-02-26 | 苏州大学 | Application of the scutelloside with sugar side chains in intake type transporter OATP1B1 regulator |
| CN115590869A (en) * | 2022-08-22 | 2023-01-13 | 天津中医药大学（Cn） | Shuganning injection and application of characteristic compound thereof in preparation of OATs (immunoglobulin of genes) inhibitor |
Citations (2)
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| CN104666412A (en) * | 2015-02-11 | 2015-06-03 | 济南大学 | Application of taking danhong injection as CYP enzyme inhibitor |
| CN104721182A (en) * | 2015-02-10 | 2015-06-24 | 广东中西达一新药开发有限公司 | Application of five-ester pill as liver transporter inhibitor |
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2016
- 2016-04-14 CN CN201610237620.6A patent/CN105769998A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104721182A (en) * | 2015-02-10 | 2015-06-24 | 广东中西达一新药开发有限公司 | Application of five-ester pill as liver transporter inhibitor |
| CN104666412A (en) * | 2015-02-11 | 2015-06-03 | 济南大学 | Application of taking danhong injection as CYP enzyme inhibitor |
Non-Patent Citations (2)
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| 刘红旭: "《心血管疾病中成药辩证应用指南》", 31 March 2009, 军事医学科学出版社 * |
| 温金华: "OATP1B1介导中药组分丹参素与瑞舒伐他汀的相互作用机制", 《药学学报》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109381468A (en) * | 2018-10-29 | 2019-02-26 | 苏州大学 | Application of the scutelloside with sugar side chains in intake type transporter OATP1B1 regulator |
| CN115590869A (en) * | 2022-08-22 | 2023-01-13 | 天津中医药大学（Cn） | Shuganning injection and application of characteristic compound thereof in preparation of OATs (immunoglobulin of genes) inhibitor |
| CN115590869B (en) * | 2022-08-22 | 2023-12-01 | 天津中医药大学 | Shuganning injection and application of characteristic compound thereof in preparation of OATs inhibitor |
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