Multiple Efflux Pumps Are Involved in the Transepithelial Transport of Colchicine: Combined Effect of P-Glycoprotein and Multidrug Resistance-Associated Protein 2 Leads to Decreased Intestinal Absorption Throughout the Entire Small Intestine

2009 ◽  
Vol 37 (10) ◽  
pp. 2028-2036 ◽  
Author(s):  
Arik Dahan ◽  
Hairat Sabit ◽  
Gordon L. Amidon
Keyword(s):  
Small Intestine ◽  
Multidrug Resistance ◽  
Intestinal Absorption ◽  
Efflux Pumps ◽  
Combined Effect ◽  
Transepithelial Transport ◽  
Entire Small Intestine ◽  
P Glycoprotein

scholarly journals Overcoming Multidrug Resistance: Flavonoid and Terpenoid Nitrogen-Containing Derivatives as ABC Transporter Modulators

Molecules ◽  
2020 ◽  
Vol 25 (15) ◽  
pp. 3364 ◽  
Author(s):  
Bruno M. F. Gonçalves ◽  
David S. P. Cardoso ◽  
Maria-José U. Ferreira
Keyword(s):  
Multidrug Resistance ◽  
Natural Product ◽  
Abc Transporter ◽  
Efflux Pumps ◽  
Cancer Resistance ◽  
Glycoprotein P ◽  
Multidrug Resistance Protein 1 ◽  
P Glycoprotein ◽  
Resistance Protein

Multidrug resistance (MDR) in cancer is one of the main limitations for chemotherapy success. Numerous mechanisms are behind the MDR phenomenon wherein the overexpression of the ATP-binding cassette (ABC) transporter proteins P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and multidrug resistance protein 1 (MRP1) is highlighted as a prime factor. Natural product-derived compounds are being addressed as promising ABC transporter modulators to tackle MDR. Flavonoids and terpenoids have been extensively explored in this field as mono or dual modulators of these efflux pumps. Nitrogen-bearing moieties on these scaffolds were proved to influence the modulation of ABC transporters efflux function. This review highlights the potential of semisynthetic nitrogen-containing flavonoid and terpenoid derivatives as candidates for the design of effective MDR reversers. A brief introduction concerning the major role of efflux pumps in multidrug resistance, the potential of natural product-derived compounds in MDR reversal, namely natural flavonoid and terpenoids, and the effect of the introduction of nitrogen-containing groups are provided. The main modifications that have been performed during last few years to generate flavonoid and terpenoid derivatives, bearing nitrogen moieties, such as aliphatic, aromatic and heterocycle amine, amide, and related functional groups, as well as their P-gp, MRP1 and BCRP inhibitory activities are reviewed and discussed.

Zinc absorption in human small intestine

1989 ◽  
Vol 256 (1) ◽  
pp. G87-G91 ◽  
Author(s):  
H. H. Lee ◽  
A. S. Prasad ◽  
G. J. Brewer ◽  
C. Owyang
Keyword(s):  
Small Intestine ◽  
Intestinal Absorption ◽  
Transport Process ◽  
Zinc Absorption ◽  
Perfusion Technique ◽  
Enhanced Absorption ◽  
Human Small Intestine ◽  
Entire Small Intestine ◽  
Rate Of Absorption ◽  
Zinc Concentrations

We determined the intestinal site of zinc absorption in humans and investigated the interaction between intestinal absorption of zinc and other solutes using the triple-lumen steady-state perfusion technique. Twenty-one healthy subjects participated in the study. During intestinal perfusion of a balanced electrolyte solution containing 0.1 mM zinc acetate, zinc absorption occurred throughout the entire small intestine. However, the jejunum had the highest rate of absorption (357 +/- 14 nM.min-1.40 cm-1) compared with the duodenum (230 +/- 33 nM.min-1.40 cm-1) and ileum (84 +/- 10 nM.min-1.40 cm-1). Over a range of zinc concentrations infused into the jejunum (0.1, 0.9, and 1.8 mM) there were linear increases in the rate of zinc absorption (P less than 0.05). Intestinal absorption of zinc was significantly stimulated by the addition of glucose (20 mM). Zinc absorption increased from 459 +/- 39 to 582 +/- 45 nM.min-1.40 cm-1 (P less than 0.05). Conversely, zinc (0.9 mM) also enhanced the absorption of glucose, which was increased from 293 +/- 43 to 447 +/- 27 microM.min-1.40 cm-1 (P less than 0.05). The enhanced absorption of zinc or glucose was not accompanied by any increase in absorption of water and sodium. In contrast, increasing the concentration of zinc in the perfusate resulted in decreased absorption of sodium and water in a dose-related manner. In conclusion, our study demonstrated that zinc absorption is concentration dependent and occurs throughout the small intestine. The jejunum has the highest rate of absorption of zinc. The interactions between absorption of zinc and other solutes suggest that the transport process of zinc is carrier mediated.

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 Synthesis of 5-oxyquinoline derivatives for reversal of multidrug resistance

2012 ◽  
Vol 8 ◽  
pp. 1700-1704 ◽  
Author(s):  
Torsten Dittrich ◽  
Nils Hanekop ◽  
Nacera Infed ◽  
Lutz Schmitt ◽  
Manfred Braun
Keyword(s):  
Multidrug Resistance ◽  
Abc Transporter ◽  
Efflux Pumps ◽  
Lead Compound ◽  
Transport Activity ◽  
Multidrug Efflux ◽  
P Glycoprotein ◽  
Multidrug Efflux Pumps ◽  
Atp Binding Cassette Transporters ◽  
Inhibitory Power

The inhibition of ABC (ATP binding cassette) transporters is considered a powerful tool to reverse multidrug resistance. Zosuquidar featuring a difluorocyclopropyl-annulated dibenzosuberyl moiety has been found to be an inhibitor of the P-glycoprotein, one of the best-studied multidrug efflux pumps. Twelve 5-oxyisoquinoline derivatives, which are analogues of zosuquidar wherein the dibenzosuberyl-piperazine moiety is replaced by either a diarylaminopiperidine or a piperidone-derived acetal or thioacetal group, have been synthesized as pure enantiomers. Their inhibitory power has been evaluated for the bacterial multidrug-resistance ABC transporter LmrCD and fungal Pdr5. Four of the newly synthesized compounds reduced the transport activity to a higher degree than zosuquidar, being up to fourfold more efficient than the lead compound in the case of LmrCD and about two times better for Pdr5.

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