scholarly journals In Vitro and In Situ Characterization of the Intestinal Absorption of Capilliposide B and Capilliposide C from Lysimachia capillipes Hemsl

Molecules ◽  
2019 ◽  
Vol 24 (7) ◽  
pp. 1227 ◽  
Author(s):  
Xu Zhang ◽  
Xiao Cheng ◽  
Yali Wu ◽  
Di Feng ◽  
Yifan Qian ◽  
...  
Keyword(s):  
Intestinal Absorption ◽  
Intestinal Permeability ◽  
Cyclosporine A ◽  
Cell Monolayer ◽  
Chinese Herb ◽  
Glycoprotein P ◽  
Drug Concentrations ◽  
Liquid Chromatography Tandem Mass ◽  
And Behavior

The goal of this investigation was to determine the processes and mechanism of intestinal absorption for capilliposide B (CAPB) and capilliposide C (CAPC) from the Chinese herb, Lysimachia capillipes Hemsl. An analysis of basic parameters, such as drug concentrations, time, and behavior in different intestinal segments was analyzed by liquid chromatography-tandem mass spectrometry (LC-MS). The susceptibility of CAPB and CAPC to various inhibitors such as P-glycoprotein (P-gp) inhibitor (verapamil); multidrug resistance-associated protein 2 (MRP2) inhibitor (indomethacin); cytochrome P450 protein 3A4 (CYP3A4) inhibitor (ketoconazole); and the co-inhibitor of P-gp, MRP2 and CYP3A4 (cyclosporine A) were assessed using both caco-2 cell monolayer and single-pass intestinal perfusion (SPIP) models. As a result, CAPB and CAPC are both poorly absorbed in the intestines and exhibited segment-dependent permeability. The intestinal permeability of CAPB and CAPC were significantly increased by the co-treatment of verapamil, indomethacin. In addition, the intestinal permeability of CAPB was also enhanced by ketoconazole and cyclosporine A. It can be concluded that the intestinal absorption mechanisms of CAPB and CAPC involve processes such as facilitated passive diffusion, efflux transporters, and enzyme-mediated metabolism. Both CAPB and CAPC are suggested to be substrates of P-gp and MRP2. However, CAPB may interact with the CYP3A4 system.

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.

In Silico Assessment of ADME Properties: Advances in Caco-2 Cell Monolayer Permeability Modeling

2019 ◽  
Vol 18 (26) ◽  
pp. 2209-2229 ◽  
Author(s):  
Hai Pham-The ◽  
Miguel Á. Cabrera-Pérez ◽  
Nguyen-Hai Nam ◽  
Juan A. Castillo-Garit ◽  
Bakhtiyor Rasulev ◽  
...  
Keyword(s):  
Intestinal Absorption ◽  
In Silico ◽  
Review Paper ◽  
Cell Monolayer ◽  
Cell Permeability ◽  
Drug Substances ◽  
Wide Range ◽  
Modeling Techniques

One of the main goals of in silico Caco-2 cell permeability models is to identify those drug substances with high intestinal absorption in human (HIA). For more than a decade, several in silico Caco-2 models have been made, applying a wide range of modeling techniques; nevertheless, their capacity for intestinal absorption extrapolation is still doubtful. There are three main problems related to the modest capacity of obtained models, including the existence of inter- and/or intra-laboratory variability of recollected data, the influence of the metabolism mechanism, and the inconsistent in vitro-in vivo correlation (IVIVC) of Caco-2 cell permeability. This review paper intends to sum up the recent advances and limitations of current modeling approaches, and revealed some possible solutions to improve the applicability of in silico Caco-2 permeability models for absorption property profiling, taking into account the above-mentioned issues.

scholarly journals In Vitro Human Onychopharmacokinetic and Pharmacodynamic Analyses of ME1111, a New Topical Agent for Onychomycosis

2017 ◽  
Vol 62 (1) ◽  
Author(s):  
Natsuki Kubota-Ishida ◽  
Naomi Takei-Masuda ◽  
Kaori Kaneda ◽  
Yu Nagira ◽  
Tsubasa Chikada ◽  
...  
Keyword(s):  
Antifungal Agent ◽  
Antifungal Agents ◽  
Nail Plate ◽  
Free Drug ◽  
Content Type ◽  
Clinical Dose ◽  
Drug Concentrations ◽  
Liquid Chromatography Tandem Mass ◽  
Human Nails

ABSTRACT ME1111 is a novel antifungal agent currently under clinical development as a topical onychomycosis treatment. A major challenge in the application of topical onychomycotics is penetration and dissemination of antifungal agent into the infected nail plate and bed. In this study, pharmacokinetic/pharmacodynamic parameters of ME1111 that potentially correlate with clinical efficacy were compared with those of marketed topical onychomycosis antifungal agents: efinaconazole, tavaborole, ciclopirox, and amorolfine. An ME1111 solution and other launched topical formulations were applied to an in vitro dose model for 14 days based on their clinical dose and administration. Drug concentrations in the deep layer of the nail and within the cotton pads beneath the nails were measured using liquid chromatography-tandem mass spectrometry. Concentrations of ME1111 in the nail and cotton pads were much higher than those of efinaconazole, ciclopirox, and amorolfine. Free drug concentrations of ME1111 in deep nail layers and cotton pads were orders of magnitude higher than the MIC90 value against Trichophyton rubrum (n = 30). Unlike other drugs, the in vitro antifungal activity of ME1111 was not affected by 5% human keratin and under a mild acidic condition (pH 5.0). The in vitro antidermatophytic efficacy coefficients (ratio of free drug concentration to MIC90s against T. rubrum) of ME1111, as measured in deep nail layers, were significantly higher than those of efinaconazole, tavaborole, ciclopirox, and amorolfine (P < 0.05). This suggests that ME1111 has excellent permeation of human nails and, consequently, the potential to be an effective topical onychomycosis treatment.

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 Intraluminal Behavior of Various Transporter Substrates in the Rat Gastrointestinal Tract

2021 ◽  
Vol 24 ◽  
pp. 563-570
Author(s):  
Yusuke Tanaka ◽  
Taiki Harada ◽  
Kazuhiro Ito ◽  
Takanori Kurakazu ◽  
Satoshi Kasaoka
Keyword(s):  
Drug Absorption ◽  
Residual Water ◽  
Glycoprotein P ◽  
Transport Studies ◽  
P Glycoprotein ◽  
Drug Concentrations ◽  
Optimal Drug ◽  
Actual Contribution ◽  
Knockout Animals

Purpose: The aim of this study was to evaluate the intraluminal behavior of various transporter substrates in different regions of the gastrointestinal (GI) tract. Methods: Drug solutions containing non-absorbable FITC-dextran 4000 (FD-4), were orally administered to rats. Residual water was sampled from the GI regions to measure the luminal drug concentration. Results: Cephalexin (CEX), a substrate of the proton-coupled oligopeptide transporter, was absorbed rapidly, and no drug was detected in the lower small intestine. Saquinavir (SQV) was primarily absorbed in the upper region. However, unlike CEX, SQV was detected even in the lower segment probably due to the efflux of SQV via P-glycoprotein (P-gp). The concentration of methotrexate (MTX) showed a similar pattern to that of non-absorbable FD-4. The low absorption of MTX was probably due to efflux via several efflux transporters, and the limited expression of proton-coupled folate transporter, an absorptive transporter for MTX, in the upper region. Conclusion: This study revealed that the luminal concentration pattern of each drug differed considerably depending on the site because of the different absorption properties and luminal volumes. Although further investigation using a specific transporter inhibitor or transporter-knockout animals are necessary to clarify the actual contribution of each transporter to the drug absorption, this information will be valuable in evaluating transporter-mediated drug absorption in in vitro transport studies for ensuring optimal drug concentrations.

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 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.

scholarly journals In VitroandIn VivoPharmacokinetics of Aminoalkylated Diarylpropanes NP085 and NP102

2016 ◽  
Vol 60 (5) ◽  
pp. 3065-3069 ◽  
Author(s):  
Liezl Gibhard ◽  
Kendrekar Pravin ◽  
Efrem Abay ◽  
Anke Wilhelm ◽  
Kenneth Swart ◽  
...  
Keyword(s):  
Liver Microsomes ◽  
Hepatic Metabolism ◽  
Pharmacokinetic Studies ◽  
Time Intervals ◽  
Content Type ◽  
Drug Concentrations ◽  
Elimination Half ◽  
Liquid Chromatography Tandem Mass ◽  
The University

ABSTRACTMalaria remains a great burden on humanity. Although significant advances have been made in the prevention and treatment of malaria, malaria control is now hindered by an increasing tolerance of the parasite to one or more drugs within artemisinin combination therapies; therefore, an urgent need exists for development of novel and improved therapies. The University of the Free State Chemistry Department previously synthesized an antimalarial compound, NP046.In vitrostudies illustrated an enhanced efficacy againstPlasmodium falciparum. However, NP046 showed low bioavailability. Efforts to enhance the bioavailability of NP046 have resulted in the synthesis of a number of aminoalkylated diarylpropanes, including NP085 and NP102. Pharmacokinetic studies were conducted in C57BL/6 mice, with 15 mg/kg NP085 or NP102 administered orally and the 5 mg/kg NP085 or NP102 administered intravenously. Blood samples were collected by means of tail bleeding at predetermined time intervals. Drug concentrations were determined using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method, and subsequently pharmacokinetic modeling was done for both compounds. NP085 and NP102 were incubatedin vitrowith human and mouse liver microsomes. Both compounds were also subjected to a parallel artificial membrane permeation assay.In vitrostudies of NP085 and NP102 illustrated that both of the compounds are rapidly absorbed and undergo rapid hepatic metabolism. The maximum concentration of drug (Cmax) obtained following oral administration of NP085 and NP102 was 0.2 ± 0.4 and 0.7 ± 0.3 μM, respectively; the elimination half-life of both compounds was 6.1 h. NP085 and NP102 showed bioavailability levels of 8% and 22%, respectively.

scholarly journals In vitro and in situ study on characterizationand mechanismofthe intestinal absorptionof 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 ◽  
Absorption Mechanism ◽  
Pharmacological Activities ◽  
In Situ Study ◽  
Concentration Time ◽  
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 andin 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.

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