Small intestinal efflux mediated by MRP2 and BCRP shifts sulfasalazine intestinal permeability from high to low, enabling its colonic targeting

Sulfasalazine is characterized by low intestinal absorption, which essentially enables its colonic targeting and therapeutic action. The mechanisms behind this low absorption have not yet been elucidated. The purpose of this study was to investigate the role of efflux transporters in the intestinal absorption of sulfasalazine as a potential mechanism for its low small-intestinal absorption and colonic targeting following oral administration. The effects of P-glycoprotein (P-gp), multidrug resistance-associated protein 2 (MRP2), and breast cancer resistance protein (BCRP) inhibitors on sulfasalazine bidirectional permeability were studied across Caco-2 cell monolayers, including dose-response analysis. Sulfasalazine in vivo permeability was then investigated in the rat jejunum by single-pass perfusion, in the presence vs. absence of inhibitors. Sulfasalazine exhibited 19-fold higher basolateral-to-apical (BL-AP) than apical-to-basolateral (AP-BL) Caco-2 permeability, indicative of net mucosal secretion. MRP2 inhibitors (MK-571 and indomethacin) and BCRP inhibitors [fumitremorgin C (FTC) and pantoprazole] significantly increased AP-BL and decreased BL-AP sulfasalazine Caco-2 transport in a concentration-dependent manner. No effect was observed with the P-gp inhibitors verapamil and quinidine. The IC50 values of the specific MRP2 and BCRP inhibitors MK-571 and FTC on sulfasalazine secretion were 21.5 and 2.0 μM, respectively. Simultaneous inhibition of MRP2 and BCRP completely abolished sulfasalazine Caco-2 efflux. Without inhibitors, sulfasalazine displayed low (vs. metoprolol) in vivo intestinal permeability in the rat model. MK-571 or FTC significantly increased sulfasalazine permeability, bringing it to the low-high permeability boundary. With both MK-571 and FTC present, sulfasalazine displayed high permeability. In conclusion, efflux transport mediated by MRP2 and BCRP, but not P-gp, shifts sulfasalazine permeability from high to low, thereby enabling its colonic targeting and therapeutic action. To our knowledge, this is the first demonstration of intestinal efflux acting in favor of oral drug delivery.

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Oleic acid increases uptake and decreases the P-gp-mediated efflux of the veterinary anthelmintic Ivermectin

Drug Research ◽

10.1055/a-0662-5741 ◽

2018 ◽

Vol 69 (03) ◽

pp. 173-180 ◽

Cited By ~ 2

Author(s):

Bilal Houshaymi ◽

Nadine Nasreddine ◽

Mamdouh Kedees ◽

Zeina Soayfane

Keyword(s):

Oleic Acid ◽

Intestinal Mucosa ◽

Drug Formulation ◽

Dependent Manner ◽

Cancer Resistance ◽

P Glycoprotein ◽

Resistance Protein ◽

Complex Micelles

AbstractThe bioavailability of ivermectin is modulated by lipid-based formulations and membrane efflux transporters such as Breast Cancer Resistance Protein and P-glycoprotein (BCRP and P-gp). We have investigated the effect of oleic acid on the uptake of ivermectin in vitro using Caco-2 cells and in vivo in the intestines of wild-type mice. Complex micelles (M) with oleic acid induced a significant increase (e. g. for M3 was 7-fold, p≤0.001) in the uptake of the drug in a time-dependent manner with no involvement of cholesterol in the mechanism. In vivo results showed a significant increase in the concentration of plasma and intestinal mucosa ivermectin (p≤0.01) in mice receiving oleic acid-based drug formulation. We also examined the expression of the drug efflux transporter, BCRP and P-gp in Caco-2 cells and found a significant decrease (p≤0.001) in their level in the presence of 5 mM oleic acid. Treatment of mice with oleic acid-based formulation showed a significant decrease in the activity of P-gp in the intestinal mucosa (p≤0.01). This study highlighted the effect of oleic acid in decreasing the expression and the activity of P-gp-mediated ivermectin efflux and in limiting the drug absorption by increasing its uptake and bioavailability in Caco-2 cells and intestine, respectively.

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Quercetin Is a Flavonoid Breast Cancer Resistance Protein Inhibitor with an Impact on the Oral Pharmacokinetics of Sulfasalazine in Rats

Pharmaceutics ◽

10.3390/pharmaceutics12050397 ◽

2020 ◽

Vol 12 (5) ◽

pp. 397

Author(s):

Yoo-Kyung Song ◽

Jin-Ha Yoon ◽

Jong Kyu Woo ◽

Ju-Hee Kang ◽

Kyeong-Ryoon Lee ◽

...

Keyword(s):

Breast Cancer ◽

Breast Cancer Resistance Protein ◽

Fold Increase ◽

Inhibitory Effect ◽

Dependent Manner ◽

Cancer Resistance ◽

Concentration Dependent Manner ◽

Resistance Protein

The potential inhibitory effect of quercetin, a major plant flavonol, on breast cancer resistance protein (BCRP) activity was investigated in this study. The presence of quercetin significantly increased the cellular accumulation and associated cytotoxicity of the BCRP substrate mitoxantrone in human cervical cancer cells (HeLa cells) in a concentration-dependent manner. The transcellular efflux of prazosin, a stereotypical BCRP substrate, was also significantly reduced in the presence of quercetin in a bidirectional transport assay using human BCRP-overexpressing cells; further kinetic analysis revealed IC50 and Ki values of 4.22 and 3.91 μM, respectively. Moreover, pretreatment with 10 mg/kg quercetin in rats led to a 1.8-fold and 1.5-fold increase in the AUC8h (i.e., 44.5 ± 11.8 min∙μg/mL vs. 25.7 ± 9.98 min∙μg/mL, p < 0.05) and Cmax (i.e., 179 ± 23.0 ng/mL vs. 122 ± 23.2 ng/mL, p < 0.05) of orally administered sulfasalazine, respectively. Collectively, these results provide evidence that quercetin acts as an in vivo as well as in vitro inhibitor of BCRP. Considering the high dietary intake of quercetin as well as its consumption as a dietary supplement, issuing a caution regarding its food–drug interactions should be considered.

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Converging effects of a Bifidobacterium and Lactobacillus probiotic strain on mouse intestinal physiology

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00401.2013 ◽

2014 ◽

Vol 307 (2) ◽

pp. G241-G247 ◽

Cited By ~ 20

Author(s):

Kevin W. Lomasney ◽

John F. Cryan ◽

Niall P. Hyland

Keyword(s):

Ion Transport ◽

Water Content ◽

Short Circuit ◽

Intestinal Transit ◽

Current Response ◽

Dependent Manner ◽

Small Intestinal Transit ◽

Ussing Chambers ◽

Small Intestinal

Evidence has grown to support the efficacy of probiotics in the management of gastrointestinal disorders, many of which are associated with dysregulated fluid and electrolyte transport. A growing body of evidence now suggests that the host microbiota and probiotics can influence intestinal ion transport and that these effects often occur in a strain-dependent manner. In this study, we sought to investigate the effects of two therapeutically relevant organisms, Bifidobacterium infantis 35624 and Lactobacillus salivarius UCC118, on small intestinal transit, fecal output and water content, transepithelial resistance (TER), and colonic secretomotor function. Mice fed either strain displayed significantly reduced small intestinal transit in vivo, though neither strain influenced fecal pellet output or water content. Colon from mice fed both organisms displayed increased colonic TER, without a concomitant change in the gene expression of the tight junction proteins claudin 1 and occludin. However, L. salivarius UCC118 selectively inhibited neurally evoked ion secretion in tissues from animals fed this particular probiotic. Consistent with this finding, the neurotoxin tetrodotoxin (TTx) significantly inhibited the short-circuit current response induced by L. salivarius UCC118 following addition to colonic preparations in Ussing chambers. Responses to B. infantis 35624 also displayed sensitivity to TTx, although to a significantly lesser degree than L. salivarius UCC118. Both strains similarly inhibited cholinergic-induced ion transport after addition to Ussing chambers. Taken together, these data suggest that B. infantis 35624 and L. salivarius UCC118 may be indicated in disorders associated with increased small intestinal transit, and, in particular for L. salivarius UCC118, neurally mediated diarrhea.

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Hepatoprotective Role of Phlogacanthus thyrsiflorus Nees as a Potential Iron Chelating Drug

International Journal of Pharmacology Phytochemistry and Ethnomedicine ◽

10.18052/www.scipress.com/ijppe.12.12 ◽

2019 ◽

Vol 12 ◽

pp. 12-22

Author(s):

Queen Saikia ◽

Manas Das ◽

Archana Saikia

Keyword(s):

Iron Overload ◽

Radical Scavenging ◽

Iron Chelation ◽

The Body ◽

Oral Drug ◽

Histopathological Analysis ◽

Dependent Manner ◽

North East

Exceeding iron levels in the body get accumulated in the liver and other vital organs that induce oxidative stress in the affected areas , which is clinically diagnosed as “iron overload”. Present study was undertaken to investigate the role of Phlogacanthus thyrsiflorus Nees, an endemic species of North-east India, in ameliorating such diseased conditions. Our results indicate that the methanolic leaf extract of Phlogacanthus thyrsiflorus (PTME) exhibits excellent iron chelation and antioxidant activities in dose dependent manner in vitro. To understand the in vivo conditions, thirty six mice were divided into six groups which were treated with differing doses of PTME. Levels of serum markers ALT and AST significantly elevates during diseased conditions but PTME treated mice have shown a marked decrease in the group (S200) by 39.24 and 17.24%. On the contrary lowering levels of liver antioxidant enzymes (GST, GSH, SOD and CAT) indicates stress. But 200mg/kg b.w of PTME treated groups restored the enzyme to optimum levels. Morphological changes were observed through histopathological analysis of liver tissues and we found significant differences in them . PTME was found to be completely nontoxic in the in vivo treatment, suggesting its feasibility as a safe oral drug. The above study suggests that PTME contributed to its free radical scavenging and iron chelation activity; however, further studies are required for the assessment of the phytoconstituents and the pathways through which it act to treat iron-overload diseases.

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Sex-Dependence in the Effect of Pharmaceutical Excipients: Polyoxyethylated Solubilising Excipients Increase Oral Drug Bioavailability in Male but Not Female Rats

Pharmaceutics ◽

10.3390/pharmaceutics11050228 ◽

2019 ◽

Vol 11 (5) ◽

pp. 228 ◽

Cited By ~ 7

Author(s):

Yang Mai ◽

Liu Dou ◽

Christine M. Madla ◽

Sudaxshina Murdan ◽

Abdul W. Basit

Keyword(s):

Ussing Chamber ◽

Drug Formulation ◽

Female Rats ◽

Oral Drug ◽

Dependent Manner ◽

Drug Bioavailability ◽

Pharmaceutical Excipients ◽

Males And Females

It is known that males and females respond differently to medicines and that differences in drug behaviour are due to inter-individual variability and sex specificity. In this work, we have examined the influence of pharmaceutical excipients on drug bioavailability in males and females. Using a rat model, we report that a portfolio of polyoxyethylated solubilising excipients (polyethylene glycol 2000, Cremophor RH 40, Poloxamer 188 and Tween 80) increase ranitidine bioavailability in males but not in females. The in vivo sex and excipient effects were reflected in vitro in intestinal permeability experiments using an Ussing chamber system. The mechanism of such an effect on drug bioavailability is suggested to be due to the interaction between the excipients and the efflux membrane transporter P-glycoprotein (P-gp), whose expression in terms of gene and protein levels were inhibited by the solubilising agents in male but not in female rats. In contrast, the non-polyoxyethylated excipient, Span 20, significantly increased ranitidine bioavailability in both males and females in a non-sex-dependent manner. These findings have significant implications for the use of polyoxyethylated solubilising excipients in drug formulation in light of their sex-specific modulation on the bioavailability of drugs that are P-gp substrates. As such, pharmaceutical research is required to retract from a ‘one size fits all’ approach and to, instead, evaluate the potential impact of the interplay between excipients and sex on drug effect to ensure effective pharmacotherapy.

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Su2080 Limited Nesting Stress Alters Maternal Behavior and In Vivo Intestinal Permeability in a Sex-Dependent Manner in Wistar Rat Pups

Gastroenterology ◽

10.1016/s0016-5085(16)32162-x ◽

2016 ◽

Vol 150 (4) ◽

pp. S629

Author(s):

Nabila Moussaoui ◽

Muriel H. Larauche ◽

Mandy Biraud ◽

Jenny Molet ◽

Mulugeta Million ◽

...

Keyword(s):

Intestinal Permeability ◽

Maternal Behavior ◽

Wistar Rat ◽

Dependent Manner ◽

Rat Pups

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Quantitative Analysis of the ABCG2 c.421C > A Polymorphism Effect on In Vivo Transport Activity of Breast Cancer Resistance Protein (BCRP) Using an Intestinal Absorption Model

Journal of Pharmaceutical Sciences ◽

10.1002/jps.24366 ◽

2015 ◽

Vol 104 (9) ◽

pp. 3039-3048 ◽

Cited By ~ 11

Author(s):

Yuta Tanaka ◽

Yoshiaki Kitamura ◽

Kazuya Maeda ◽

Yuichi Sugiyama

Keyword(s):

Breast Cancer ◽

Quantitative Analysis ◽

Intestinal Absorption ◽

Breast Cancer Resistance Protein ◽

Absorption Model ◽

Cancer Resistance ◽

Transport Activity ◽

Resistance Protein

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Effect of Water-Loading on the Performance of Polyethylene Glycol as a Marker of Small Intestinal Permeability

Clinical Science ◽

10.1042/cs0890299 ◽

1995 ◽

Vol 89 (3) ◽

pp. 299-303 ◽

Cited By ~ 1

Author(s):

Tariq H. Iqbal ◽

Mark A. Cox ◽

Kenneth O. Lewis ◽

Brian T. Cooper

Keyword(s):

Polyethylene Glycol ◽

Intestinal Permeability ◽

Volume Of Distribution ◽

Differential Rate ◽

Water Loading ◽

Collection Period ◽

Small Intestinal ◽

Renal Tubular ◽

The Individual

1. Polyethylene glycol has been used extensively to measure small intestinal permeability in vivo. However, polyethylene glycol seems to traverse the intestinal mucosa in much greater quantities than sugar molecules of equivalent Mr. In addition, the recovery of the lowest Mr polymers of administered polyethylene glycol has been found to be both low and unreliable. 2. To compare the behaviour of a range of polyethylene glycol polymers with sugar probes in vivo, a combined polyethylene glycol/mannitol/lactulose probe was administered sequentially to healthy individuals in the fasted state and under conditions of water-loading. Timed hourly urine collections were made for 6 h. 3. Mannitol and lactulose recoveries were all within the normal range and were unaffected by coadministration of water. The lactulose/mannitol recovery ratios did not vary significantly over the 6 h collection period. In contrast, the recovery of total polyethylene glycol was significantly greater when subjects were water-loaded. Futhermore, proportionally greater quantities of polyethylene glycol Mr 370 than Mr 854 were recovered towards the end of the collection period than at the start. 4. Our results show that, in contrast to lactulose and mannitol, excretion of low—medium Mr polyethylene glycol polymers is highly dependent on coadministration of water. Futhermore, the differential rate of excretion of the low compared with the high Mr polyethylene glycol polymers suggests that the volume of distribution of the individual polymers may vary with Mr, and smaller polyethylene glycol molecules may undergo considerable renal tubular reabsorption.

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Crystal-liquid Fugacity Ratio as a Surrogate Parameter for Intestinal Permeability

Journal of Pharmacy & Pharmaceutical Sciences ◽

10.18433/j3ks4p ◽

2016 ◽

Vol 19 (3) ◽

pp. 312 ◽

Cited By ~ 1

Author(s):

Parvin Zakeri-Milani ◽

Zohreh Fasihi ◽

Jafar Akbari ◽

Ensieh Jannatabadi ◽

Mohammad Barzegar-Jalali ◽

...

Keyword(s):

Dissolution Rate ◽

Intestinal Absorption ◽

Intestinal Permeability ◽

Scanning Calorimetry ◽

Mole Percent ◽

Intrinsic Dissolution ◽

Intrinsic Dissolution Rate ◽

Close Relationship ◽

Dose Number

Background: We assessed the feasibility of using crystal-liquid fugacity ratio (CLFR) as an alternative parameter for intestinal permeability in the biopharmaceutical classification (BCS) of passively absorbed drugs. Methods: Dose number, fraction of dose absorbed, intestinal permeability, and intrinsic dissolution rate were used as the input parameters. CLFR was determined using thermodynamic parameters i.e., melting point, molar fusion enthalpy, and entropy of drug molecules obtained using differential scanning calorimetry. Results: The CLFR values were in the range of 0.06-41.76 mole percent. There was a close relationship between CLFR and in vivo intestinal permeability (r > 0.8). CLFR values of greater than 2 mole percent corresponded to complete intestinal absorption. Applying CLFR versus dose number or intrinsic dissolution rate, more than 92% of tested drugs were correctly classified with respect to the reported classification system on the basis of human intestinal permeability and solubility. Conclusion: This investigation revealed that the CLFR might be an appropriate parameter for quantitative biopharmaceutical classification. This could be attributed to the fact that CLFR could be a measure of solubility of compounds in lipid bilayer which was found in this study to be directly proportional to the intestinal permeability of compounds. This classification enables researchers to define characteristics for intestinal absorption of all four BCS drug classes using suitable cutoff points for both intrinsic dissolution rate and crystal-liquid fugacity ratio. Therefore, it may be used as a surrogate for permeability studies. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

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