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Aim To study the transport mechanism of bergenin passing through blood-brain barrier ( BBB ) . Methods MTT assay was used to investigate the tox-icity of bergenin on MDCK-MDRl cells. Molecular docking was used to predict the binding mode and effect ability of bergenin with P-gp. In vitro MDCK-MDRl cell monolayer model was used to analyze trans¬port characteristics of bergenin and the effect of con¬centration, time and verapamil (a P-gp inhibitor) on the transport of bergenin. Results Bergenin was non-toxic to MDCK-MDRl cells within the concentration of 5 to 40 jjunol • L . There was hydrogen-bond and hy-drophobic interaction between P-gp and bergenin, and P-gp-bergenin was more stable than P-gp-verapamil. The P value of bergenin transported from AP to BL (PappAP
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Chinese materia medica is mostly taken orally. The permeability of a drug’s biofilm (e.g. cell membrane) reflects its ability of absorption and transportation in the body. It is of guiding significance to evaluate the membrane permeability of the active components of Chinese materia medica by using appropriate drug permeation model, so as to clarify, the oral absorption and transport mechanism of active ingredients, pharmacodynamic substance basis and dosage form design. The evaluation method of oral drug membrane permeability, as well as the application of various methods in Chinese medicine was summarized for reference in this review.
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Objective: To investigate transport mechanism of cyperotundone in Caco-2 cell model and provide experimental basis for clinical application of Cyperi Rhizoma. Method: The toxicity of cyperotundone with different concentrations to Caco-2 cells was investigated by methyl thiazolyl tetrazolium (MTT) colorimetry, in order to determine the concentration of administration in transport test. The content of cyperotundone was determined by liquid chromatography-mass spectrometry (LC-MS) with apparent permeability coefficient (Papp) and cumulative transport capacity as indexes. The chromatographic conditions were as following:mobile phase of acetonitrile (A)-water (B) for gradient elution (0-1.5 min, 35%A; 1.5-2 min, 35%-90%A; 2-4 min, 90%A; 4-4.1, 90%-35%A; 4.1-8 min, 35%A), the flow rate at 0.3 mL · min-1, injection volume of 1 μL, and temperature of column at 30℃. The mass spectrometric conditions was electrospray ionization (ESI) and positive ion mode, the detection ions of cyperotundone and osthole (internal standard substance) were m/z 219.2-110.9 and m/z 245.0-189.0, respectively. Effect of concentration of cyperotundone, administration time, ethylenediamine tetraacetic acid (EDTA) and P-glycoprotein (P-gp) inhibitor on the transmembrane transport of cyperotundone on in vitro cell model were investigated. Result: Cyperotundone didn't have significant toxicity to Caco-2 cells at 3-90 mg · L-1 after incubation for 4 h. The transportion of cyperotundone in Caco-2 cell model was related to the concentration and time to a certain extent, its Papp was higher than 1×10-6 cm · s-1, which indicated that absorption of cyperotundone was good, the efflux rate (ER) of cyperotundone was 0.5-1.5.There was no significant difference in bidirectional Papp of cyperotundone after the addition of cell bypass transport inhibitor (EDTA) and P-gp transport inhibitor (verapamil). Conclusion: The transport mechanism of cyperotundone in Caco-2 cell model is mainly passive diffusion, and cell bypass transport and P-gp are not involved in its transport.
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Organic anion transporters(OAT)belong to a family of poly-specific transporters mainly locate in barrier epithelia such as renal proximal tubule.The solute transporter superfamily(SLC)is mainly distributed in the renal proximal convoluted tubules and located in other organs such as the brain,liver and placenta.They are mainly responsible for the reabsorption and secretion of en?dogenous and exogenous organic anions.OAT interact with endogenous metabolic end products such as urate and acidic neutrotransmit?ter metabolites,as well as a multitude of widely used drugs,and play an important role in the excretion and pharmacokinetics of drugs. This article reviews the recent progress in the research of the members of the OAT family.
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Isorhapontigenin (ISO) is suggested to have many different kinds of pharmacology activities, such as anti-inflammatory effect, anti-oxidation effect and anti-cancer effect. This paper mainly discussed the transport mechanism of ISO in Caco-2 cell models. The concentration of ISO was determined by UPLC method with PDA detector at 310 nm, and then the apparent permeability coefficient Papp was calculated. The cytotoxic of different concentrations of ISO was investigated on Caco-2 cells to determine the concentration of drug administration. The effects of ISO concentration, time, temperature and transporter inhibitors on the transport of ISO were investigated. The test results showed that, ISO didn't have significant cytotoxicity at 10-60 μmol•L ⁻¹ in 14 hours. The transportation of ISO on Caco-2 cells was related to the concentration to a certain extent. Papp of ISO was higher than 10×10-6 cm•s ⁻¹ and ISO was absorbed easily by Caco-2 cells. The transport volume of ISO at BL side reached maximum at 3 h and was slightly decreased at 6 h. Papp (AP-BL) and Papp(BL-AP) at 4 ℃ were lower than those at 37 ℃. Papp (AP-BL) of ISO was significantly increased after adding P-gp inhibitor verapamil and Papp (BL-AP) of ISO was significantly decreased after adding MRP-2 inhibitor (probenecid or MK-571). The results suggested that transport mode of ISO was mainly passive diffusion in Caco-2 cell models, and P-gp and MRP may be involved in the transport of ISO.
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Bentysrepinine (Y101), a derivative of phenylalanine dipeptide, is a novel drug candidate for the treatment of hepatitis B virus (HBV) infection. Our previous preclinical pharmacokinetic study showed that its in vivo absorption and distribution characteristics were probably related to transmembrane transport after Y101 was administered intragastically in rats. In this study, Caco-2 and MDCK-MDR1 cell models were used to investigate interactions between Y101 and P-gp through the apparent permeation coefficient (Papp) and efflux ratio (RE); the results showed that Y101 was a substrate of P-gp. In addition, gene-transfected cell models, HEK293-hOATP1B1, HEK293-hOATP2B1 and CHO-PEPT1 were used to evaluate the affinity to OATP1B1,
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Fritillaria thunbergii Miq. has been widely used in traditional Chinese medicine for its expectorant, antitussive, antiinflammatory and analgesic properties. Moreover, modern pharmacological studies have demonstrated that F. thunbergii Miq. has efficacy in the treatment of leukemia and cancers of the liver and cervix. Although the alkaloid, peimine, is largely responsible for these pharmacological effects, it has very low oral bioavailability. The aim of this study was to investigate the intestinal absorption of peimine in Caco-2 cell monolayers. Having demonstrated that peimine is non-toxic to Caco-2 cells at concentrations <200 μmol/L, the effect of peimine concentration, pH, temperature, efflux transport protein inhibitors and EDTA-Na2 on peimine transport were studied. The results show that peimine transport is concentration-dependent; that at pH 6.0 and 7.4, the P app(AP-BL) of peimine is not significantly different but the P app(BL-AP)) is; that both P app(AP-BL) and P app(BL-AP) at 4 °C are significantly higher than their corresponding values at 37 °C; that the P-glycoprotein (P-gp) inhibitors, verapamil and cyclosporin A, increase absorption of peimine; and that EDTA-Na2 has no discernible effect. In summary, the results demonstrate that the intestinal absorption of peimine across Caco-2 cell monolayers involves active transport and that peimine is a substrate of P-gp.
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Objective: To study the mechanisms of absorption and transport of 3-acetyl-11-keto-β-boswellic acid (AKBA) from Boswellia carterif in Caco-2 cell, MDCK-MDR1, and MDCK-Wild cell models. Methods: The Caco-2, MDCK-MDR1, and MDCK-Wild cell monolayer models were used to study the bi-directional transport of AKBA in apical (AP)→basal (BL) or BL→AP; The concentration of AKBA was measured by LC-MS/MS and apparent permeability coefficient (Papp) was calculated. Results: Papp (AP→BL) and Papp (BL→AP) values of AKBA (50 μmol/L) in Caco-2 cell model were 7.9 × 10-7 and 1.5 × 10-7 cm/s, respectively; Papp (AP→BL) and Papp (BL→AP) values of AKBA (50 μmol/L) in MDCK-MDR1 cell model were 2.6 × 10-7 and 0.8 × 10-7 cm/s, respectively; Papp (AP→BL) and Papp (BL→AP) of AKBA (50 μmol/L) in MDCK-Wild cell model was 2.4 × 10-7 and 0.6 × 10-7 cm/s, respectively; The rates of efflux (RE) for AKBA in Caco-2 and MDCK-MDR1 cell monolayers were both smaller than 2. Conclusion: AKBA is not the substrate of P-gp and its absorption rate is low. AKBA is absorbed through the intestinal epithelial cells by active transport absorption and passive diffusion possibly.
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Multidrug resistance to chemotherapeutic drugs is an important reason for clinical chemotherapy failure. The mechanisms of the classical drug resistance such as P-gp, MRP have been clarified. Hence, it is very important to further study the non-classical mechanism of multidrug resistance. We introduced the effects on MDR, the possible mechanisms of glutathione and related enzymes, as well as the relationship between structure of GSH analogues and the transport activity in this paper.