Acute regulation of apical ABC transporters in the gut. Potential influence on drug bioavailability

Domínguez, Camila Juliana; Tocchetti, Guillermo Nicolás; Rigalli, Juan Pablo; Mottino, Aldo D.

doi:10.1016/j.phrs.2020.105251

Cited by 8 publications

(8 citation statements)

References 126 publications

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“…as well as the organ and cell type in which they are expressed. For example, members of the ABCB and ABCC subfamilies are expressed in physiological barriers such as intestine and blood–brain interfaces to restrict the entry or mediate the exit of harmful endogenous molecules or xenobiotics [ 3 , 4 ]. Overexpression of these ABC transporters has been reported in several cancers and is responsible for the multidrug resistance (MDR) phenotype of cancer cells [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

Role of ABCA7 in Human Health and in Alzheimer’s Disease

Dib

Pahnke

Gosselet

2021

IJMS

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Several studies, including genome wide association studies (GWAS), have strongly suggested a central role for the ATP-binding cassette transporter subfamily A member 7 (ABCA7) in Alzheimer’s disease (AD). This ABC transporter is now considered as an important genetic determinant for late onset Alzheimer disease (LOAD) by regulating several molecular processes such as cholesterol metabolism and amyloid processing and clearance. In this review we shed light on these new functions and their cross-talk, explaining its implication in brain functioning, and therefore in AD onset and development.

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Section: Introductionmentioning

confidence: 99%

Role of ABCA7 in Human Health and in Alzheimer’s Disease

Dib

Pahnke

Gosselet

2021

IJMS

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“… 37 , 38 P-glycoprotein (P-gp), multidrug resistance protein 2 (MRP2) and breast cancer resistance protein (BCRP) are the main ABC transporters distributed in the intestinal barrier. 39 , 40 Among them, P-gp is most expressed in the colon and ileum, and MRP2 and BCRP are highly expressed in the small intestine. 41 The drug efflux mediated by these ABC transporters limits the absorption of the substrate drug and has a significant impact on the efficacy of oral drugs.…”

Section: Discussionmentioning

confidence: 99%

Development of Paeonol Liposomes: Design, Optimization, in vitro and in vivo Evaluation

Huang¹,

Zhai²,

Yang³

et al. 2022

IJN

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Background Ulcerative colitis (UC) is one of the intractable diseases recognized by the World Health Organization, and paeonol has been proven to have therapeutic effects. However, the low solubility of paeonol limits its clinical application. To prepare and optimize paeonol liposome, study its absorption mechanism and the anti-inflammatory activity in vitro and in vivo, in order to provide experimental basis for the further development of paeonol into an anti-inflammatory drug in the future. Methods Paeonol loaded liposomes were prepared and optimized by thin film dispersion-ultrasonic method. The absorption mechanism of paeonol-loaded liposomes was studied by pharmacokinetics, in situ single-pass intestinal perfusion and Caco-2 cell monolayer model, the anti-inflammatory activity was studied in a mouse ulcerative model. Results Box-Behnken response surface methodology permits to screen the best formulations. The structural and morphological characterization showed that paeonol was entrapped inside the bilayer in liposomes. Pharmacokinetic studies found that the AUC 0-t of Pae-Lips was 2.78 times than that of paeonol suspension, indicating that Pae-Lips significantly improved the absorption of paeonol. In situ single intestinal perfusion and Caco-2 monolayer cell model results showed that paeonol was passively transported and absorbed, and was the substrate of P-gp, MRP2 and BCRP, and the Papp value of Pae-Lips was significantly higher than that of paeonol. In vitro and in vivo anti-inflammatory experiments showed that compared with paeonol, Pae-Lips exhibited excellent anti-inflammatory activity. Conclusion In this study, Pae-Lips were successfully prepared to improve the oral absorption of paeonol. Absorption may involve passive diffusion and efflux transporters. Moreover, Pae-Lips have excellent anti-inflammatory activity in vitro and in vivo, which preliminarily clarifies the feasibility of further development of Pae-Lips into oral anti-inflammatory drugs.

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“…Fast and reversible modulation of the activity of efflux transporters is of interest to formulation scientists and pharmacologists for the drug delivery of transporter substrates [38]. Changes to the transporter expression can be regulated by (i) changes in their protein expression (long-term regulation) or (ii) changes that do not modify the total amount of protein (acute regulation) [38], by transcriptional or post-transcriptional changes. Interestingly, clear changes are seen in the P-gp, BCRP and MRP2 expression 30 min after the feeding interventions.…”

Section: Discussionmentioning

confidence: 99%

“…These findings suggest that a dosage form could be designed which releases a specific transporter inhibitor to inhibit their expression [40], followed by a drug substrate. Short-term reversibility of the transporter could ensure the normal physiological functioning of the intestinal tract after the dose has been absorbed [38]. A proposed mechanism for P-gp inhibition is the inhibition of ATPase activity, as P-gp is an energyactivated protein.…”

Section: Discussionmentioning

confidence: 99%

A Non-Nutritive Feeding Intervention Alters the Expression of Efflux Transporters in the Gastrointestinal Tract

et al. 2021

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Intestinal interactions with nutrients, xenobiotics and endogenous hormones can influence the expression of clinically relevant membrane transporters. These changes in the gastrointestinal (GI) physiology can in turn affect the absorption of numerous drug substrates. Several studies have examined the effect of food on intestinal transporters in male and female humans and animal models. However, to our knowledge no studies have investigated the influence of a non-nutritive fibre meal on intestinal efflux transporters and key sex and GI hormones. Here, we show that a fibre meal increased the acute expression of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug-resistance-associated protein-2 (MRP2) in small intestinal segments in both male and female Wistar rats. Enzyme-linked immunosorbent assays were used for the protein quantification of efflux transporters and hormonal plasma concentration. In male rats, the fibre meal caused the plasma concentration of the GI hormone cholecystokinin (CCK) to increase by 75% and the sex hormone testosterone to decrease by 50%, whereas, in contrast, the housing food meal caused a decrease in CCK by 32% and testosterone saw an increase of 31%. No significant changes in the hormonal concentrations, however, were seen in female rats. A deeper understanding of the modulation of efflux transporters by sex, food intake and time can improve our understanding of inter- and intra-variability in the pharmacokinetics of drug substrates.

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Acute regulation of apical ABC transporters in the gut. Potential influence on drug bioavailability

Cited by 8 publications

References 126 publications

Role of ABCA7 in Human Health and in Alzheimer’s Disease

Role of ABCA7 in Human Health and in Alzheimer’s Disease

Development of Paeonol Liposomes: Design, Optimization, in vitro and in vivo Evaluation

A Non-Nutritive Feeding Intervention Alters the Expression of Efflux Transporters in the Gastrointestinal Tract

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