Polysorbate 20 increases oral absorption of digoxin in wild-type Sprague Dawley rats, but not in mdr1a(-/-) Sprague Dawley rats

Nielsen, Carsten Uhd; Abdulhussein, Ahmed A.; Colak, Dilan; Holm, René

doi:10.1016/j.ijpharm.2016.09.011

Cited by 21 publications

(42 citation statements)

References 46 publications

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“…In wild type Sprague-Dawley rats, polysorbate 20 significantly increased the oral bioavailability of digoxin (Nielsen et al, 2016) and etoposide (Al-Ali et al, 2018). However, oral co-administration of polysorbate 20 with digoxin or etoposide in mdr1a deficient Sprague-Dawley rats has had no impact on the bioavailability, compared to the oral administration of these P-gp substrates without the surfactant (Al-Ali et al, 2018;Nielsen et al, 2016). This suggests that polysorbate 20 mediated P-gp inhibition is the reason for the increased bioavailability in wild type rats.…”

Section: Introductionmentioning

confidence: 96%

“…Even though most work on the ability of nonionic surfactants to inhibit P-gp has been performed in vitro, a few studies have investigated if surfactants administered orally to animals could increase the bioavailability of P-gp substrates, such as digoxin (Cornaire et al, 2004;Nielsen et al, 2016;Zhang et al, 2003), doxorubicin (Al-Saraf et al, 2016), and etoposide (Akhtar et al, 2017;Al-Ali et al, 2018). In wild type Sprague-Dawley rats, polysorbate 20 significantly increased the oral bioavailability of digoxin (Nielsen et al, 2016) and etoposide (Al-Ali et al, 2018). However, oral co-administration of polysorbate 20 with digoxin or etoposide in mdr1a deficient Sprague-Dawley rats has had no impact on the bioavailability, compared to the oral administration of these P-gp substrates without the surfactant (Al-Ali et al, 2018;Nielsen et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

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Nonionic surfactants increase digoxin absorption in Caco-2 and MDCKII MDR1 cells: Impact on P-glycoprotein inhibition, barrier function, and repeated cellular exposure

Al-Ali

Steffansen

Holm

et al. 2018

International Journal of Pharmaceutics

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Nonionic surfactants commonly used in pharmaceutical formulations may have P-glycoprotein (P-gp) inhibiting and/or permeation enhancing effects. The present work aims to distinguish these effects and assess the degree of cellular recovery after multiple exposures to nonionic surfactants. The investigated surfactants were polysorbates (PS): PS20, PS40, PS60, PS65, PS80 and PS85; monosaccharide-based: lauroyl methyl glucamide and n-nonyl-β-D-glucopyranoside; or disaccharide-based: lauryl-β-D-maltoside and trehalose 6-laurate. Bi-directional permeability studies of digoxin and mannitol, and calcein-AM efflux assay were performed in cell cultures. Cellular recovery was evaluated by continuous measurements of transepithelial electrical resistance (TEER) in Caco-2 cell monolayers. Polysorbates with one fatty acid chain decreased the efflux of digoxin through P-gp inhibition in MDCKII MDR1 cells. Mono- and di-saccharide-based surfactants, in a dose dependent manner, enhanced digoxin absorptive permeability without decreasing the secretory permeability in Caco-2 cells, suggesting that the surfactants had a transcellular permeation enhancing effect. Caco-2 cell monolayers recovered to different degrees of 60-100% of the initial TEER values. Calcein-AM assay was found to be non-predictive to surfactants influence on digoxin permeability across cell monolayers. In conclusion, these results may assist, in a mechanism-based, selection of suitable surfactants for formulating oral dosage forms to enhance the absorption of low bioavailable P-gp substrates.

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Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Nonionic surfactants increase digoxin absorption in Caco-2 and MDCKII MDR1 cells: Impact on P-glycoprotein inhibition, barrier function, and repeated cellular exposure

Al-Ali

Steffansen

Holm

et al. 2018

International Journal of Pharmaceutics

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“…This is probably due to the small droplets of ME characterized by a big surface area, which leads to an increased solubility and absorption. Moreover, nonionic surfactants, such as labrasol and Tween 20, also contributed to increase extract solubility, avoid degradation phenomena, extend the contact time with the absorption site, increase endocytic and transcellular pathways, and inhibit P-glycoprotein efflux activity [30][31][32]. As in the case of PAMPA, also in this case, the recovery resulted above 80 %, as required for acceptable in vitro permeation prediction (▶ Table 6).…”

Section: Resultsmentioning

confidence: 91%

“…For this reason, Tween 20 and labrasol were chosen as the surfactant and cosurfactant, respectively, as well as considering their high solubilizing capacity toward the SC extract. Tween 20 (also known as polysorbate 20) is a nonionic surfactant used to increase oral bioavailability of drugs due to its capacity to improve solubility and inhibit ABC transporter-mediated cellular efflux [30,31]. Labrasol consists of a small fraction of mono-, di-, and triglycerides and mainly PEG-8 (MW 400) mono-and diesters of caprylic and capric acid.…”

Section: Resultsmentioning

confidence: 99%

Enhanced Solubility and Permeability of Salicis cortex Extract by Formulating as a Microemulsion

et al. 2018

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A microemulsion system was developed and investigated as a novel oral formulation to increase the solubility and absorption of Salicis cortex extract. This extract possesses many pharmacological activities, in particular, it is beneficial for back pain and osteoarthritic and rheumatic complaints. In this work, after qualitative and quantitative characterization of the extract and the validation of an HPLC/diode array detector analytical method, solubility studies were performed to choose the best components for microemulsion formulation. The optimized microemulsion consisted of 2.5 g of triacetin, as the oil phase, 2.5 g of Tween 20 as the surfactant, 2.5 g of labrasol as the cosurfactant, and 5 g of water. The microemulsion was visually checked, characterized by light scattering techniques and morphological observations. The developed formulation appeared transparent, the droplet size was around 40 nm, and the -potential result was negative. The maximum loading content of Salicis cortex extract resulted in 40 mg/mL. Furthermore, storage stability studies and an digestion assay were performed. The advantages offered by microemulsion were evaluated using artificial membranes and cells, i.e., parallel artificial membrane permeability assay and a Caco-2 model. Both studies proved that the microemulsion was successful in enhancing the permeation of extract compounds, so it could be useful to ameliorate the bioefficacy of Salicis cortex.

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“…Nielsen et al investigated the ability of Tween 20 to increase oral digoxin absorption in vivo after its co-administration to Sprague Dawley rats. 44) They concluded that the amount of Tween 20 required to increase the oral bioavailability of digoxin in vivo was 10% of the dosing volume. Since Tween 20 did not enhance digoxin absorption in Sprague Dawley mdr1a(−/−) rats, the increase observed in digoxin bioavailability in vivo in rats appears to be mediated by the modulation of P-gp transport activity rather than through the solubilization of digoxin.…”

Section: Discussionmentioning

confidence: 99%

Influence of Polysorbate 60 on Formulation Properties and Bioavailability of Morin-Loaded Nanoemulsions with and without Low-Saponification-Degree Polyvinyl Alcohol

Ikeuchi-Takahashi

Kobayashi

Ishihara

et al. 2018

Biological & Pharmaceutical Bulletin

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The aim of the present study was to investigate the influence of polysorbate 60 (Tween 60) on the development of morin-loaded nanoemulsions to improve the oral bioavailability of morin. Nanoemulsions were prepared using Tween 60 and polyvinyl alcohol (PVA) as emulsifiers, and medium chain triglycerides (MCT) as the lipid base. Low-saponification-degree PVA (LL-810) was also added to stabilize dispersed droplets. MCT-LL810 nanoemulsion containing LL-810 was prepared with a reduced amount of Tween 60. However, the area under the blood concentration-time curve (AUC) of MCT-LL810 (0.18) nanoemulsion containing a small amount of Tween 60 did not increase because the absorption of morin was limited by P-glycoprotein (P-gp)-mediated efflux. MCT-LL810 (0.24) nanoemulsion containing a large amount of Tween 60 showed the highest AUC, dispersed droplets containing Tween 60 may have been transported into epithelial cells in the small intestine, and P-gp transport activity appeared to be suppressed by permeated Tween 60. Based on the plasma concentration profile, dispersed droplets in MCT-LL810 (0.24) nanoemulsion permeated more rapidly through the mucus layer and the intestinal membrane than MCT (0.24) nanoemulsion without LL-810. In conclusion, a novel feature of Tween 60 incorporated into the dispersed droplets of a nanoemulsion interacting with P-gp was demonstrated herein. Dispersed droplets in MCT-LL810 (0.24) nanoemulsion containing LL-810 permeated rapidly through the mucus layer and intestinal membrane, and Tween 60 incorporated in dispersed droplets interacted with P-gp-mediated efflux, increasing the bioavailability of morin.Key words nanoemulsion; morin; polyvinyl alcohol; bioavailability; P-glycoprotein Morin (2′,4′,3,5,7-pentahydroxyflavonoid) is one of the flavonoids widely found in fruits, vegetables, tea, and numerous therapeutic herbs.1) Its wide spectrum of biological activities, including anti-inflammatory, anti-cancer, antioxidant, antiangiogenic, anti-hypertensive, and anti-clastogenic activities, have been reported. [2][3][4][5][6][7][8] We previously demonstrated that a treatment with morin induced basal nitric oxide production and rapid improvements in endothelial function in diabetic mice.9) Morin has been suggested to improve the development of endothelial dysfunction by diabetes. However, the absolute bioavailability of morin after its oral administration is very low (less than 1%), and this may be attributed to its low aqueous solubility, P-glycoprotein (P-gp)-mediated efflux, and low intestinal permeability. [10][11][12] Various approaches have been attempted in order to increase the area under the blood concentration-time curve (AUC) of low bioavailability drugs after their oral administration. Nanoemulsion systems have received increasing attention as appropriate carriers for insoluble active compounds to increase bioavailability and modify drug release characteristics. [13][14][15] Improvements in the solubility of drugs into nanoemulsion components such as the oil phase and surfactants repre...

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Polysorbate 20 increases oral absorption of digoxin in wild-type Sprague Dawley rats, but not in mdr1a(-/-) Sprague Dawley rats

Cited by 21 publications

References 46 publications

Nonionic surfactants increase digoxin absorption in Caco-2 and MDCKII MDR1 cells: Impact on P-glycoprotein inhibition, barrier function, and repeated cellular exposure

Nonionic surfactants increase digoxin absorption in Caco-2 and MDCKII MDR1 cells: Impact on P-glycoprotein inhibition, barrier function, and repeated cellular exposure

Enhanced Solubility and Permeability of Salicis cortex Extract by Formulating as a Microemulsion

Influence of Polysorbate 60 on Formulation Properties and Bioavailability of Morin-Loaded Nanoemulsions with and without Low-Saponification-Degree Polyvinyl Alcohol

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