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Modulation on the P-Glycoprotein in the Intestine and Drug Transport Via the Intestine by Combined Use of Radix Glycyrrhizae and Flos Genkwa

Author: HuangZuoZuo
Tutor: LiGuoFeng
School: Southern Medical University,
Course: Pharmacy
Keywords: P-glycoprotein Licorice Genkwa In vitro diffusion cell In situ experiments Rhodamine 123
CLC: R285.5
Type: Master's thesis
Year: 2009
Downloads: 317
Quote: 2
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Abstract

The background and purpose of P-glycoprotein (P-glycoprotein, P-gp) is to belong to the ABC (ATP-binding cassette) transporter superfamily of energy-dependent membrane proteins, with a molecular weight of 170 kDa, can play the role of the efflux pump, the cells The compounds within the inverse concentration gradient is transported to the extracellular domain, thereby reducing the concentration of the drug in the cell. The addition is highly expressed in tumor cells, P-gp in normal body tissues and organs such as the liver, kidney, placenta, brain, testes and intestinal brush border film parts have a high level of expression. Present in the intestinal epithelial cell brush border membrane of P-gp can drug from serosal side pump back to the mucosal side into the intestine discharged drugs through the membrane to reduce the absorption, lower blood concentration. By intestinal absorption by the intestinal mucosa regulation of P-gp drug can inhibit the activity of the intestinal mucosa of P-gp and increase the absorption and improve bioavailability. It has been confirmed that many drugs are intestinal mucosa of P-gp inhibitors such as verapamil, ring cytochalasin A, quinidine, some of the surface active agent. The Chinese medicine Eighteen Chinese medicine sector followed the millennia medication contraindications. Studies have shown that the front and rear the licorice with anti-drug combination has a different role of cytochrome P450. Interestingly, a P-gp substrate specificity is largely cytochrome P450 isoenzymes (CYP3A _1-3) similar, the two have many overlapping substrates, such as rifampicin, lidocaine, digoxin, and cyclosporin. So, these anti-drug combination around may produce different regulation of P-gp of the intestinal mucosa, which may be the anti-drug combination to the cause of the clinical toxicity. The literature search showed that at home and abroad has not been by to explore research between the intestinal mucosal expression of P-gp with Chinese herbal medicines rationality report, explore traditional Chinese medicine anti-drug combination of increased toxicity after P-gp expression changes high academic value. Select eighteen anti medicine on licorice and genkwa of this topic as a model drug research. Body In situ experiments, analysis of the expression of P-gp on the intestinal mucosa the licorice genkwa combination before and after using in vitro diffusion cell method (Ussing chamber). Typical substrates of P-gp drug rhodamine 123 (R123) and the next cell pathway drugs sodium fluorescein (CF) as the test drug, easier to analyze because these two compounds have the visible range of fluorescent, the detection sensitivity is high, as its transporter way markers have been widely used in various studies. Expectations indirectly Description the licorice genkwa combination around the laws, and the regulation of P-gp clarify the possible mechanism of the two combined to cause increased toxicity. Content and results of traditional Chinese medicine based on a different origin, different processing methods, the quality is very different and therefore should be the first Chinese medicine used in the experiment licorice and genkwa of identification, and prepared a certain concentration of licorice liquid genkwa solution, licorice genkwa, together fried liquid licorice genkwa is combined liquid by HPLC to establish maps to ensure consistency in the quality of the experimental process of Chinese herbal medicines. Mobile phase of methanol: water = 1:9, detection wavelength: 254 nm, and flow rate: 1 mL · min ^{-1 , the injection volume was 20 μL. The HPLC experiments results found the licorice genkwa differences together decoction combined liquid map, whether this difference will cause the of different boiling process different from the regulation of P-gp on the intestinal mucosa, and need to be follow-up experimental study. Vitro Ussing chamber experimental evaluation R123 CF by air absorption and secretion directions when intestinal mucosa cumulative transmittance and apparent permeability coefficient (Papp), determination of different concentrations of verapamil (P-gp classic inhibitors) R123 and CF by jejunal mucosal permeability. Results R123 secretion direction of the transporter in the jejunum permeability coefficient greater than that of the absorption direction (approximately four), indicating that its transport in the intestine is secreted mainly described the presence of a pump system. The transshipment of CF is not the intestinal mucosa of P-gp-mediated paracellular route, the secretion direction and absorb directions Papp approximately equal (ER = 1.08); test concentrations of verapamil can significantly improve the absorption of R123, and can significantly inhibit the secretion direction transporter, CF transporter in the intestinal mucosa was not affected. These results are consistent with the foreign literature, Ussing chamber experiments in our laboratory conditions is feasible. The rats fed different concentrations in the liquid, one week after all kinds of liquid used in vitro Ussing chamber method for R123 and CF by jejunal mucosal permeability. It was found that low concentrations of licorice solution can increase to R123 jejunal mucosal absorption, secretion not statistically significant (P> 0.05); the genkwa liquid decoction liquid and merge solution can reduce R123 secretion direction through However, the increase in the absorption direction through. Licorice of CF by empty intestinal mucosa through impact while the other three groups of drug solution can significantly reduce the the CF absorption and secretion direction permeability. Establish a high-performance liquid - fluorescence detection method for determination of plasma concentration of R123. Mobile phase of acetonitrile-1% triethylamine (28:72), a flow rate of 1.0 mL · min ^{-1 ; fluorescence detector wavelength of 485 nm (excitation wavelength) and 546 nm (emission wavelength) . R123 detection concentration in 15.625 ~ 500 ng · mL ^{-1 The linear range of a good relationship, a standard curve for S =, 5420.2C 341 494 (R ^{2 = 0.9997), the lowest detection limit 5 ng · mL ^{-1 , plasma sample extraction recoveries and recoveries ideal intra day RSD were less than 4%, within 24h after the sample extraction and freeze-thaw stability is good. In situ experiments in vivo, rats fed all kinds of liquid R123 and CF changes in drug concentration in plasma was measured to calculate various pharmacokinetic parameters. Was found the the licorice group of R123 highest plasma concentration C _{in max}, the area under the curve of the AUC _0-240min and the bioavailability F with the control group showed no significant difference, while genkwa group decoction group and the combined group C _max the the AUC _0-240min and F were higher than the control group (P <0.01), and the aggregate the fried group consolidated group AUC < sub> 0-240 and F genkwa group, an increase of nearly half of the difference was statistically significant (P <0.01), and co-fried group consolidated group had no significant (P> 0.05); rats after gavage genkwa, CF pharmacokinetic parameters with the control group showed no significant difference. Conclusions and discuss the combined results of in vitro and in vivo experiments, can infer genkwa can significantly inhibit the expression of P-gp. Clinical, Daphne compatibility easy to produce drug resistance of anticancer drugs, or made of tumor drug resistance reversal agents to increase the anti-cancer properties; can also try the preparation of the drug, due to join daphne spend, improve the absorption of P-gp substrate drugs. The role genkwa of CF may the one hand, inhibit the absorption genkwa inhibiting secretion, on the other hand, have reduced the amount of absorption and secretion, leading to the ultimate bioavailability was no difference with the control group, which results with genkwa of P -gp inhibitors are not contradictory. Chinese medicine is known as the ten nine grass, no grass no party, \The experiments show that licorice slight inhibition of P-gp, licorice may be through direct or indirect regulation of P-gp, changing the permeability of the gastrointestinal mucosa, causing the increase in different drug absorption. This is the future of licorice \transshipment way drugs through the gastrointestinal mucosa penetration and absorption of the impact of possible mechanisms, widely used for clinical Licorice other drugs to improve efficacy to provide more evidence. Combination of licorice genkwa be compared with genkwa, enhanced P-gp inhibition However, the decoction the merger of two processing methods for P-gp. Description together decoction combined liquid chromatogram of both the regulation of P-gp on the intestinal mucosa impact. We can infer licorice and genkwa of compatibility toxic, Licorice the genkwa have synergies, so some genkwa in the chemical composition of the enhanced role of inhibition of P-gp expression, so genkwa in the secretion of toxic ingredients to reduce the increased absorption which led other hand, Daphne and licorice combined toxic licorice in some toxic substances (P-gp substrate) genkwa absorption increase, which has yet to be the future of further toxic effects; experiment. Research, time, energy, and other reasons, there are also many deficiencies. For example, in the experiment only analyzed of licorice genkwa combination of jejunal mucosal P-gp, there is no other bowel; rat gavage Time only select 7 d, and no animal experiments do different gavage time; experiment only qualitative analysis not to do quantitative analysis. These shortcomings can be remedied in a future study.}}}}}

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