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Application of tetrahydropalmatine enantiomers in preparation of P-glycoprotein inhibitor

A glycoprotein inhibitor, the technology of tetrahydropalmatine, applied in the application field of preparing P-glycoprotein inhibitors, can solve the change of pharmacokinetic properties of anti-tumor drugs, and the inability of P-gp inhibitors to clinical tumor chemotherapy Adjuvant therapy, affecting the dosage design of chemotherapy drugs and other issues, to achieve the effect of increasing indications and non-addiction

Inactive Publication Date: 2011-06-22
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Many second-generation P-gp reversal agents (such as PSC833, VX-710) have strong reversal effects, but because they are substrates of CYP3A4, they can competitively inhibit most antineoplastic drugs (most antineoplastic drugs is also a CYP3A4 substrate), the combination of these reversal agents and antineoplastic drugs will cause changes in the pharmacokinetic properties of antineoplastic drugs, thereby affecting the dose design of chemotherapeutic drugs
Therefore, at present, P-gp inhibitors cannot really be applied to the adjuvant therapy of clinical tumor chemotherapy.

Method used

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  • Application of tetrahydropalmatine enantiomers in preparation of P-glycoprotein inhibitor
  • Application of tetrahydropalmatine enantiomers in preparation of P-glycoprotein inhibitor
  • Application of tetrahydropalmatine enantiomers in preparation of P-glycoprotein inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] Example 1 Effects of tetrahydropalmatine (THP) enantiomers on rhodamine 123 transport in MDCK and MDCK / MDR1 cells

[0019] 1.1 Seeding cells on a permeable support

[0020] Select MDCK and MDCK / MDR1 cells in logarithmic growth phase (see: Liu Yao, et al. Establishment of Martin Darby dog ​​kidney epithelial cell line with high expression of P-glycoprotein. Chinese Journal of Pharmaceutical Sciences, 2009,44(21):1608 -13), digest and collect cells. Resuspend the cells with fresh medium and adjust the cell density to 2.0 × 10 5 mL -1 . Add 0.5ml of cell suspension to the top of the permeable support, and add 1.5ml of fresh medium to the bottom. The medium was changed every other day, and after 7 days of culture, a fully differentiated cell monolayer was obtained.

[0021] 1.2 Determination of the transmembrane resistance of monolayer cells

[0022] (1) Place HBSS in a 37°C water bath and preheat it to 37°C;

[0023] (2) Put the electrode into HBSS preheated to ...

Embodiment 2

[0034] Example 2 Accumulation and transport of tetrahydropalmatine enantiomers in cells with high expression of MDR1

[0035] 2.1 The accumulation of THP in Bcap37 and Bcap37 / MDR1 cells

[0036] Bcap37 / MDR1 is a human breast cancer cell that highly expresses MDR1 (P-gp). The study examined the effect of the P-gp inhibitor quinine on the tetrahydropalmatine racemate ((±) - THP), (-)-THP accumulation in Bcap37 and Bcap37 / MDR1 cells. The results showed that: when quinine was added to the culture medium, (±) - There was no significant change in the accumulation of THP and (-)-THP in the cells ( P> 0.05), see figure 1 and figure 2 , the data in the figure are expressed as mean±SD, n=3. The above results suggest: (±) - THP and (-)-THP themselves are not substrates of P-glycoprotein.

[0037] 2.2 THP transport in MDCK / MDR1 cells

[0038] According to the method in Example 1, the transport of THP in MDCK / MDR1 cells was investigated, and its efflux rate was calculated. The ...

Embodiment 3

[0039] Example 3 Effects of Tetrahydropalmatine Enantiomers on Main Metabolic Enzymes of Phase I Metabolism

[0040] 3.1 Investigation of the inhibitory effect of THP enantiomers on mouse CYP450 enzymes

[0041] Take an appropriate amount of mouse liver microsomes, dilute it to a certain protein concentration with a regeneration system, then add the probe substrates of each CYP450 enzyme to the system, mix well and add a series of concentrations (1, 5, 12.5, 25, 50, 100, 125 μmol / Lol / L (-)-THP and (+)-THP, and a series of classic inhibitors of CYP450 enzymes (CYP1A2: 0.5~5 μmol / Lol / L α-naphthoflavone; CYP2C: 0.1~ 5 μmol / Lol / L vofloxamine; CYP2D22: 1~10 μmol / Lol / L quinidine sulfate; CYP2E1: 0.5~5 μmol / Lol / L 4-methylpyrazole; CYP3A11: 0.1~2 μmol / Lol / L ketone Conazole), and an equal volume of solvent DMSO was used as a blank control, so that the final volume of the incubation system was 200 μl, and the content of DMSO was controlled at 0.3%. After pre-incubating in a constant ...

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Abstract

The invention provides application of tetrahydropalmatine enantiomers in preparation of P-glycoprotein inhibitor. The tetrahydropalmatine is one of main active ingredients of the Chinese herbal medicine rhizoma corydalis and comprises L-tetrahydropalmatine and D-tetrahydropalmatine. The research shows that the tetrahydropalmatine enantiomers can obviously inhibit the P-gp function, but the tetrahydropalmatine enantiomers are not the P-gp substrates; the tetrahydropalmatine enantiomers can obviously increase the concentration of anti-tumor medicine adriamycins in medicament-resistant tumor cells and reverse the multi-medicament resistance of tumor cells and do not have obvious effects of inhibiting and inducing main medicament metabolic enzymes of liver microsomes, so that the racemes, laevo isomers or dextro isomers of the tetrahydropalmatine enantiomers can be used as auxiliary medicaments for tumor chemotherapy, and the range of indications of the tetrahydropalmatine is expanded; and simultaneously, the invention provides the medicament for the assistant treatment for tumors, which alleviates pain, improves curative effect and is not addictive, for tumor patients.

Description

technical field [0001] The invention belongs to the application of medicine, and relates to the application of tetrahydropalmatine enantiomers in the preparation of P-glycoprotein inhibitors. technical background [0002] Tumor multidrug resistance (multidrug resistance, MDR) is one of the main reasons for the failure of chemotherapy, so finding and developing multidrug resistance reversal agents is an adjuvant therapy to overcome tumor drug resistance and improve the efficacy of chemotherapy. Studies have shown that the main mechanism of tumor drug resistance is the high expression of efflux-type drug transporters in tumor cells, such as P-glycoprotein (P-glycoprotein, P-gp), multidrug resistance-associated protein 1 (Multidrug resistance-associated protein 1). , MRP1), etc., these "drug efflux pumps" will unidirectionally expel chemotherapeutic drugs entering the tumor cells, and the tumor cells will thus acquire drug resistance [1,2] . Because P-gp and MRP1 have broad-s...

Claims

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Application Information

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IPC IPC(8): A61K31/4375A61P35/00A61K31/704
Inventor 孙思源李丽萍黄善定赵鸣孙冬黎刘瑶曾苏蒋惠娣
Owner ZHEJIANG UNIV
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