scholarly journals Elucidation of the Intestinal Absorption Mechanism of Loganin in the Human Intestinal Caco-2 Cell Model

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Renjie Xu ◽  
Yichu Yuan ◽  
Jia Qi ◽  
Jia Zhou ◽  
Xiaowen Guo ◽  
...  
Keyword(s):  
Intestinal Absorption ◽  
Cell Model ◽  
Iridoid Glycosides ◽  
Cell Monolayer ◽  
Efflux Transporter ◽  
Cancer Resistance ◽  
Absorption Mechanism ◽  
Glycoprotein P ◽  
Active Efflux ◽  
Basolateral Side

Loganin, iridoid glycosides, is the main bioactive ingredients in the plant Strychnos nux-vomica L. and demonstrates various pharmacological effects, though poor oral bioavailability in rats. In this study, the intestinal absorption mechanism of loganin was investigated using the human intestinal Caco-2 cell monolayer model in both the apical-to-basolateral (A-B) and the basolateral-to-apical (B-A) direction; additionally, transport characteristics were systematically investigated at different concentrations, pHs, temperatures, and potential transporters. The absorption permeability (PappAB) of loganin, which ranged from 12.17 to 14.78 × 10−6cm/s, was high at four tested concentrations (5, 20, 40, and 80μM), while the major permeation mechanism of loganin was found to be passive diffusion with active efflux mediated by multidrug resistance-associated protein (MRP) and breast cancer resistance protein (BCRP). In addition, it was found that loganin was not the substrate of efflux transporter P-glycoprotein (P-gp) since the selective inhibitor (verapamil) of the efflux transporter exhibited little effects on the transport of loganin in the human intestinal Caco-2 cells. Meanwhile, transport from the apical to the basolateral side increased 2.09-fold after addition of a MRP inhibitor and 2.32-fold after addition of a BCRP inhibitor. In summary, our results clearly demonstrate, for the first time, a good permeability of loganin in the human intestinal Caco-2 cell model and elucidate, in detail, the intestinal absorption mechanism and the effects of transporters on iridoid glycosides compounds.

Mechanism of the Intestinal Absorption of Six Flavonoids from Zizyphi Spinosi Semen Across Caco-2 Cell Monolayer Model

2020 ◽  
Vol 21 (8) ◽  
pp. 633-645
Author(s):  
Panpan Song ◽  
Sa Xiao ◽  
Yanqing Zhang ◽  
Junbo Xie ◽  
Xusheng Cui
Keyword(s):  
Intestinal Absorption ◽  
Cell Monolayer ◽  
Chinese Herb ◽  
Monocarboxylate Transporter ◽  
Absorption Mechanism ◽  
Glycoprotein P ◽  
Significant Information ◽  
Transport Assay ◽  
Energy Dependent ◽  
Monolayer Model

Background: Flavonoid compounds are one kind of active ingredients isolated from a traditional Chinese herb Zizyphi spinosae semen (ZSS). Studies have shown that ZSS flavonoids have significant antioxidant effects. Methods: In this study, the Caco-2 cell monolayer model was constructed to investigate the intestinal absorption characteristics and mechanism of Isovitexin (IV), Swertisin (ST), Isovitexin-2''-O-β-D-glucopyranoside (IVG), Spinosin (S), 6'''-p-coumaroylspinosin (6-CS) and 6'''-feruloylspinosin (6-FS). Results: The results of the bidirectional transport assay showed that the six flavonoids have good intestinal absorption in a near-neutral and 37°C environment, and the absorbability in descending order was 6-FS>6- CS>IVG>S>IV>ST. The results of carrier inhibition experiments and transport kinetics indicated that the absorption mechanism of six flavonoids was energy-dependent monocarboxylate transporter (MCT)-mediated active transport. In particular, the para-cellular pathway also participated in the transport of IV, ST, IVG and S. Furthermore, the efflux process of six flavonoids was mediated by P-glycoprotein (P-gp) and multidrug resistance protein (MRP), which may result in a decrease of bioavailability. Conclusion: Our findings provide significant information for revealing the relationship between the intestinal absorption mechanism of flavonoids and its structure as well as laying a basis for the research of flavonoid preparations.

scholarly journals Intestinal Absorption Mechanisms of Five Flavonoids from Malus hupehensis (Pamp.) Rehd. Extracts in Situ Single-Pass Intestinal Perfusion and in Vitro Caco-2 Cell Model

2020 ◽  
Author(s):  
Hui Yang ◽  
Zhishu Tang ◽  
Jiangxue Cheng ◽  
Jing Wang ◽  
Junbo Zou ◽  
...  
Keyword(s):  
Cell Model ◽  
Paracellular Pathway ◽  
Intestinal Perfusion ◽  
Cancer Resistance ◽  
Absorption Mechanism ◽  
Single Pass ◽  
Malus Hupehensis ◽  
Intestinal Segments

Abstract Background: Previous studies have shown that Malus hupehensis (Pamp.) Rehd. extracts have anti-oxidant, anti-aging and other effects, its bioavailability is low, however its absorption mechanism is still unclear. To investigate the absorption properties of hyperin, quercitrin, phloridzin, quercetin, and phloretin in total flavonoids of Malus hupehensis (Pamp.) Rehd. Extracts. Methods: In situ single-pass intestinal perfusion model and in vitro Caco-2 cell model were used in this study. The effects of concentration of the extract, administration time, temperature, different intestinal segments, paracellular pathway were analyzed, and the effect of efflux inhibitors, such as the P-gp inhibitor verapamil, the multidrug resistance protein2 (MRP2) inhibitor indomethacin, the breast cancer resistance protein (BCRP) inhibitor reserpine, on the transport were evaluated. As well as EDTA, a tight junction regulator, was studied.Results: The results indicated that the jejunum was the optimal absorption intestine segment of quercitrin, phloridzin, and phloretin. And the greatest absorption intestine segment of quercetin was ileum. Furthermore, it was found that the absorption mechanisms of phloridzin in extract was involved in passive diffusion and the mediation of P-gp and MRP2 should not be neglected. The absorption mechanisms of quercetin and phloretin from extract involved active transport and were accompanied by the participation of efflux transporters, such as P-gp, MRP2 and BCRP. And also the paracellular pathway was involved in hyperin and quercitrin. Conclusion: The absorption mechanisms of five flavonoids from Malus hupehensis (Pamp.) Rehd. extract are related to the concentration of the drugs, intestinal segments, and efflux protein.

scholarly journals In vitro and in situ study on characterizationand mechanismofthe intestinal absorptionof 2,3,5,4'-tetrahydroxy-stilbene-2-O-β-D-glucoside

2020 ◽  
Author(s):  
Cheng Wang ◽  
Yimeng Zhou ◽  
Xiaohong Gong ◽  
Li Zheng ◽  
Yunxia Li
Keyword(s):  
Intestinal Absorption ◽  
High Performance ◽  
Cell Monolayer ◽  
Absorption Mechanism ◽  
Pharmacological Activities ◽  
Concentration Time ◽  
In Situ Experiments ◽  
Basic Parameters

Abstract Background: 2,3,5,4'-tetrahydroxystilbence-2-O-β-D-glucoside(TSG) is a polyhydroxyphenolic compound, which exhibited a broad spectrum of pharmacological activities, such asanti-inflammatory, anti-depression, anti-oxidation and anti-atherosclerosis.However, the compound had poor bioavailability and the underlying absorption mechanisms had not been studied. Therefore, the purpose of this study was to investigate the intestinal absorption mechanism of TSG. Methods: This study used Caco-2 cell monolayer model and single-passintestinal perfusion modelto explore the gastrointestinal absorption mechanisms of TSG. The effects of basic parameters such as drug concentration, time and pH on the intestinal absorption of TSG were analyzed by high performance liquid chromatography.The absorption susceptibility of TSG to three inhibitors, P-gp inhibitors verapamil hydrochloride and quinidine, and MRP2 inhibitor probenecid were also assessed. Results: TSG was poorly absorbed in the intestines and the absorption of TSG in stomach is much higher than that in intestine. Both in vitro and in situ experiments showed that the absorption of TSG was saturated with increasing concentration and it was better absorbed in a weakly acidic environment pH 6.4. Moreover, TSG interacts with P-gp and MRP2, and TSG was not only the substrate of the P-gp and MRP2, but also affected the expression of P-gp and MRP2. Conclusions: It wasconcluded that the gastrointestinalabsorption mechanisms ofTSG involved processes passive transport and the participation ofefflux transporters.

scholarly journals The absorption of oral morroniside in rats: In vivo, in situ and in vitro studies

2019 ◽  
Vol 69 (2) ◽  
pp. 287-296 ◽  
Author(s):  
Shan Xiong ◽  
Jinglai Li ◽  
Yanling Mu ◽  
Zhenqing Zhang
Keyword(s):  
Iridoid Glycosides ◽  
Specific Substrate ◽  
Sprague Dawley ◽  
Glycoprotein P ◽  
Cornus Officinalis ◽  
Sd Rats ◽  
Basolateral Side

Abstract Morroniside is one of the most important iridoid glycosides from Cornus officinalis Sieb. et Zucc. In the present study, the pharmacokinetics and bioavailability studies of morroniside were conducted on Sprague-Dawley (SD) rats. A rat in situ intestinal perfusion model was used to characterize the absorption of morroniside. Caco-2 cells were used to examine the transport mechanisms of morroniside. The pharmacokinetic study of morroniside exhibited linear dose-proportional pharmacokinetic characteristics and low bioavailability (4.3 %) in SD rats. Its average Peff value for transport across the small intestinal segments changed from (3.09 ± 2.03) × 10−6 to (4.53 ± 0.94) × 10−6 cm s−1. In Caco-2 cells, the Papp values ranged from (1.61 ± 0.53) × 10−9 to (1.19 ± 0.22) × 10−7 cm s−1 for the apical to basolateral side and the Pratio values at three concentrations were all lower than 1.2. Morroniside showed poor absorption and it might not be a specific substrate of P-glycoprotein (P-gp).

scholarly journals Alleviating the Intestinal Absorption of Rhein in Rhubarb through Herb Compatibility in Tiaowei Chengqi Tang in Caco-2 Cells

2018 ◽  
Vol 2018 ◽  
pp. 1-7 ◽  
Author(s):  
Ying Peng ◽  
Min Fan ◽  
Chongsheng Peng ◽  
Mengyue Wang ◽  
Xiaobo Li
Keyword(s):  
Intestinal Absorption ◽  
Breast Cancer Resistance Protein ◽  
Critical Role ◽  
Cell Monolayer ◽  
Intracellular Uptake ◽  
Clinical Use ◽  
Cancer Resistance ◽  
Detoxification Mechanism ◽  
Resistance Protein ◽  
Insight Into

Tiaowei Chengqi Tang (TWCQT) is composed of rhubarb, processed liquorice, and Natrii Sulfas, which is used as a purgative in traditional Chinese medicine (TCM). This study focused on the intestinal absorption of rhein in disassembly of the TWCQT extracts through the Caco-2 cell monolayer model to explicate the possible detoxification mechanism of herb-herb compatibility in TWCQT. The results showed that the intestinal absorption of rhein occurred through active diffusion, and rhein might be composed of breast cancer resistance protein (BCRP) substrates. The extract of processed liquorice increased the exclusion rate and reduced intracellular uptake of rhein. The consistent results observed in TWCQT further implied that processed liquorice in TWCQT could suppress the absorption of rhein across the Caco-2 cell monolayer. It has therefore been concluded that the active ingredients of processed liquorice may play a critical role in reducing the intestinal absorption of rhein to alleviate the toxicity of rhubarb in TWCQT. Because of BCRP’s involvement in rhein transport, we conjectured that some components in processed liquorice could inhibit the transport of rhein, possibly by mediating BCRP. These results would provide new insight into this ancient drug combination in toxicity reduction and clinical use.

scholarly journals In vivo and in vitro study on characterization and mechanism of the intestinal absorption of 2,3,5,4'-tetrahydroxy-stilbene-2-O-β-D-glucoside

2019 ◽  
Author(s):  
Cheng Wang ◽  
Yimeng Zhou ◽  
Xiaohong Gong ◽  
Li Zheng ◽  
Yunxia Li
Keyword(s):  
Intestinal Absorption ◽  
High Performance ◽  
Cell Monolayer ◽  
In Vitro Study ◽  
Absorption Mechanism ◽  
Pharmacological Activities ◽  
Concentration Time ◽  
Basic Parameters

Abstract Background: 2,3,5,4'-tetrahydroxystilbence-2-O-β-D-glucoside(TSG) is a polyhydroxyphenolic compound, which exhibits a broad spectrum of pharmacological activities, such asanti-inflammatory, anti-depression, anti-oxidation and anti-atherosclerosis.However, the compound has poor bioavailability and the underlying absorption mechanisms has not been studied. Therefore, the purpose of this study was to investigate the intestinal absorption mechanism of TSG. Methods: This study used the Caco-2 cell monolayer model and the single-passintestinal perfusion modelto explore the intestinal absorption mechanisms of TSG. The effects of basic parameters such as drug concentration, time and pH on the intestinal absorption of TSG were analyzed by high performance liquid chromatography.In addition, the susceptibility of TSG absorption process to treatment with three inhibitors, such as P-gp inhibitors verapamil hydrochloride and quinidine, and the MRP2 inhibitor probenecid were also assessed. Results: TSG is poorly absorbed in the intestines and the absorption of TSG in the stomach is much higher than that in the intestine. Both in vivo and in vitro experiments showed that the absorption of TSG was saturated with increasing concentration. and it was better absorbed in a weakly acidic environment with a pH of 6.4. Moreover, TSG interacts with P-gp and MRP2, and TSG is not only the substrate of the P-gp and MRP2, but also affects the expression of P-gp and MRP2. Conclusions: It can be concluded that the intestinal absorption mechanismsofTSG involve processes passive transport and the participation of efflux transporters.

scholarly journals Intestinal Absorption of Geniposide and Inhibition of Transporter-P-GP Across the Caco-2 Monolayer

2020 ◽  
Author(s):  
Yanhong Bu ◽  
hong wu ◽  
MingHui Sun ◽  
Heng Zhang ◽  
Ran Deng ◽  
...  
Keyword(s):  
Intestinal Absorption ◽  
Cell Monolayer ◽  
Hplc Method ◽  
Transepithelial Transport ◽  
Absolute Bioavailability ◽  
Glycoprotein P ◽  
Gardenia Jasminoides ◽  
P Glycoprotein ◽  
Bioactive Component ◽  
Bidirectional Transport

Abstract Background: Geniposide (GE) is the main bioactive component of Gardenia jasminoides Ellis, which has many pharmacological effects, such as anti-inflammatory, anti-oxidation, and anti-angiogenesis. GE has low absolute bioavailability after oral administration, and speculated that GE might have an effect on P-glycoprotein (P-gp) described in our previous study. However, intestinal absorption characteristics involved in the Caco-2 cells of GE are still unknown. Therefore, we aimed to investigate absorption mechanisms of GE and the effects on P-gp. Methods: By establishing the Caco-2 cells model and HPLC method, bidirectional transport of GE in the different conditions and the presence of P-gp inhibitors－verapamil were conducted to observe its absorption mechanisms. Transport assays of digoxin, a P-gp substrate, were also performed in the presence of GE or verapamil. The effects of GE on the function and expression of P-gp were analyzed by flow cytometry and Western blot using rhodamine-123 (rho-123) and the antibody, respectively. Results: Both absorption and secretion of GE were positively correlated with concentration and time at Caco-2 cell monolayer. The Papp of bidirectional transport was decreased in low temperature and the Papp(BL-AP) of GE decreased significantly in the presence of verapamil. Meanwhile, the ER value was higher than 1.5. In addition, in the bidirectional transport of digoxin, the values of Papp(BL-AP) and ER decreased significantly in the presence of GE, just like verapamil. GE increased the intracellular accumulation of rho-123 and also have a significant decrease on P-gp expression. Conclusion: Transepithelial transport mechanism of GE in Caco-2 cell monolayer is mainly passive diffusion and P-gp mediated active transportation. GE was a potential inhibitor of P-gp, can inhibit transport of digoxin and the function and expression of P-gp.

scholarly journals A study of intestinal absorption of bicyclol in rats: active efflux transport and metabolism as causes of its poor bioavailability

2008 ◽  
Vol 11 (3) ◽  
pp. 97 ◽  
Author(s):  
Wei Tan ◽  
Hui Chen ◽  
Jinping Hu ◽  
Yan Li
Keyword(s):  
Cell Monolayer ◽  
Intestinal Perfusion ◽  
Efflux Transport ◽  
Glycoprotein P ◽  
Active Efflux ◽  
The Poor ◽  
P Glycoprotein ◽  
Respective Contribution ◽  
Monolayer Model

Purpose.To determine the possible mechanism of poor bioavailability of bicyclol, and clarify the respective contribution of P- glycoprotein (P-gp) and Cytochrome 3A (CYP3A). Methods. Rat in situ single-pass intestinal perfusion and Caco-2 cell monolayer model with selective inhibitors of CYP3A and P-gp were employed. Results. In rat intestinal perfusion, bicyclol (50µM) appearance in mesenteric blood (Pblood) was increased 3, 12, 16-fold by addition of inhibitors of P-gp (LSN335984), CYP3A ( troleandomycin, TAO) or P-gp and CYP3A (Cyclosporin A, CsA), respectively, whereas permeability of midazolam (CYP3A substrate only) was unchanged by LSN335984 and increased 5 and 1-fold by TAO and CsA. In addition, the metabolized fraction of bicyclol was decreased by 9%, 33%, 36% with inhibitor of P-gp, CYP3A, or P-gp and CYP3A. Moreover, the cumulative amount of bicyclol in mesenteric blood was increased at concentration range 10-100µM of bicyclol in perfusate. The ER (Pappba/Pappab) value of bicyclol in Caco-2 monolayer was significantly deceased by LSN335984 and CsA. Conclusion. The poor bioavailability of bicyclol was mostly due to the P-gp mediated efflux and metabolism by CYP3A in intestine, while CYP3A was believed to make more contribution than P-gp.

scholarly journals Investigation of the Functional Role of P-Glycoprotein in Limiting the Oral Bioavailability of Lumefantrine

2013 ◽  
Vol 58 (1) ◽  
pp. 489-494 ◽  
Author(s):  
Wahajuddin ◽  
Kanumuri S. R. Raju ◽  
Sheelendra P. Singh ◽  
Isha Taneja
Keyword(s):  
Intestinal Absorption ◽  
Oral Absorption ◽  
Stability Study ◽  
Cytochrome P450 3A ◽  
Glycoprotein P ◽  
Active Efflux ◽  
P Glycoprotein

ABSTRACTIn the quest to explore the reason for the low and variable bioavailability of lumefantrine, we investigated the possible role of P-glycoprotein (P-gp) in lumefantrine intestinal absorption. Anin situsingle-pass intestinal perfusion study in rats with the P-gp inhibitor verapamil or quinidine and an ATPase assay with human P-gp membranes indicated that lumefantrine is a substrate of P-gp which limits its intestinal absorption. To confirm these findings, anin vivopharmacokinetic study was performed in rats. The oral administration of verapamil (10 mg/kg of body weight) along with lumefantrine caused a significant increase in its bioavailability with a concomitant decrease in clearance. The increase in bioavailability of lumefantrine could be due to inhibition of P-gp and/or cytochrome P450 3A in the intestine/liver by verapamil. However, in a rat intestinal microsomal stability study, lumefantrine was found to be resistant to oxidative metabolism. Further, anin situpermeation study clearly showed a significant role of P-gp in limiting the oral absorption of lumefantrine. Thus, the increase in lumefantrine bioavailability with verapamil is attributed in part to the P-gp-inhibitory ability of verapamil. In conclusion, lumefantrine is a substrate of P-gp, and active efflux by P-gp across the intestine partly contributed to the low/variable bioavailability of lumefantrine.

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