Investigations of Piperazine Derivatives as Intestinal Permeation Enhancers in Isolated Rat Intestinal Tissue Mucosae

Stuettgen, Vivien; Brayden, David J.

doi:10.1208/s12248-020-0416-9

Cited by 10 publications

(11 citation statements)

References 53 publications

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“…In a previous work by Asmar et al , a time-dependent decrease TEER is an indicator of tight junction disassembly [ 49 ]. This is further supported by the work of Stuettgen et al who showed that the addition of phenylpiperazine (PPZ) and its derivatives induced concentration-dependent decreases in TEER leading to an increase paracellular uptake across the intestine [ 21 ]. Therefore, by comparing our results, it is postulated that the enhancement in ibuprofen absorption across small intestine may involve the time-dependent dilation of tight junction between the epithelial cells leading to enhanced drug transport via the paracellular pathway [ 50 ].…”

Section: Resultsmentioning

confidence: 75%

“…TEER was used to assess the effect of drug presence on the intestinal barrier function as well as indicators of intercellular passage of the intestinal mucosa [ 19 ]. Since the major route of ions occur paracellularly, TEER has been used for assessing the permeability of tight junctions [ 20 ] and its association with an increase in paracellular permeability [ 21 ].…”

Section: Resultsmentioning

confidence: 99%

“…The small droplet size confers larger colloidal surface area that promote solubility and dissolution rate which ultimately translate to enhance mucosal permeability across the intestinal tracts [ 16 , 17 , 18 ]. Besides that, nanoemulsions circumvents issues such flocculation and coalescence during long-term storage because the nanometer-sized droplets are more kinetically stable relative to conventional emulsion systems [ 19 , 20 , 21 ]. Construction of pseudoternary phase diagram is a critical step in the development of such lipid-based formulation.…”

Section: Introductionmentioning

confidence: 99%

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Development and characterisation of ibuprofen-loaded nanoemulsion with enhanced oral bioavailability

Anuar

Sabri

Effendi

et al. 2020

Heliyon

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Lipophilic compounds constitute a majority of therapeutics in the pipeline of drug discovery. Despite possessing enhanced efficacy and permeability, some of these drugs suffer poor solubility necessitating the need of a suitable drug delivery system. Nanoemulsion is a drug delivery system that provides enhanced solubility for poorly soluble drugs in an attempt to improve the oral bioavailability. The purpose of this study is to develop a nanoemulsion system using ibuprofen as a model drug in order to investigate the potential of this colloidal system to enhance the absorption of poorly water-soluble drugs. Ibuprofen loaded-nanoemulsion with different drug concentrations (1.5, 3 and 6% w/w) were formulated from olive oil, sucrose ester L-1695 and glycerol using D-phase emulsification technique. A pseudoternary phase diagram was utilised to identify the optimal excipient composition to formulate the nanoemulsion system. In vitro diffusion chamber studies using rodent intestinal linings highlighted improved absorption profile when ibuprofen was delivered as nanoemulsion in comparison to microemulsions and drug-in-oil systems. This was further corroborated by in vivo studies using rat model that highlighted a two-fold increase in ibuprofen absorption when the drug was administered as a nanoemulsion relative to drug-in-oil system. On the other hand, when ibuprofen was administered as microemulsions, only a 1.5-fold increase in absorption was observed relative to drug-in-oil system. Thus, this study highlights the potential of using nanoemulsion as a drug delivery system to enhance the oral bioavailability of hydrophobic drugs.

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Section: Resultsmentioning

confidence: 75%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Development and characterisation of ibuprofen-loaded nanoemulsion with enhanced oral bioavailability

Anuar

Sabri

Effendi

et al. 2020

Heliyon

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“…One of the chosen permeation enhancers is phenylpiperazine (PPZ), which we and others have found to improve paracellular permeation by tight junction rearrangement using in vitro (Caco‐2 monolayers) and ex vivo (rodent intestinal tissue in Ussing chambers) models. 20 , 21 , 22 We also used sodium deoxycholate (SDC), which is a bile salt that enhances permeability via membrane fluidization and tight junction rearrangement as determined using in vitro and ex vivo models. 23 , 24 Then, we compared them to sodium caprate (C 10 ), as its nontoxicity and efficacy are extensively characterized in literature.…”

Section: Resultsmentioning

confidence: 99%

Long‐term daily oral administration of intestinal permeation enhancers is safe and effective in mice

Fein

Gleeson

Cochran

et al. 2022

Bioengineering & Transla Med

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Although protein drugs are powerful biologic therapeutics, they cannot be delivered orally because their large size and hydrophilicity limit their absorption across the intestinal epithelium. One potential solution is the incorporation of permeation enhancers into oral protein formulations; however, few have advanced clinically due to toxicity concerns surrounding chronic use. To better understand these concerns, we conducted a 30‐day longitudinal study of daily oral permeation enhancer use in mice and resultant effects on intestinal health. Specifically, we investigated three permeation enhancers: sodium caprate (C 10 ), an industry standard, as well as 1‐phenylpiperazine (PPZ) and sodium deoxycholate (SDC). Over 30 days of treatment, all mice gained weight, and none required removal from the study due to poor health. Furthermore, intestinal permeability did not increase following chronic use. We also quantified the gene expression of four tight junction proteins (claudin 2, claudin 3, ZO‐1, and JAM‐A). Significant differences in gene expression between untreated and permeation enhancer‐treated mice were found, but these varied between treatment groups, with most differences resolving after a 1‐week washout period. Immunofluorescence microscopy revealed no observable differences in protein localization or villus architecture between treated and untreated mice. Overall, PPZ and SDC performed comparably to C 10 , one of the most clinically advanced enhancers, and results suggest that the chronic use of some permeation enhancers may be therapeutically viable from a safety standpoint.

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“…Furthermore, there is a connection between 5-HT 1B, 4 receptors and the mTOR pathway, but the promotion of cell viability by 5-HT seems to be less related to mTOR. Although these 5-HTR antagonists had no effect on cell viability in studies with other cells [49][50][51][52][53], further research is needed on MAC-T…”

Section: Discussionmentioning

confidence: 98%

Effect of serotonin on the cell viability of the bovine mammary alveolar cell-T (MAC-T) cell line

Dong¹,

Liu²,

Miao³

et al. 2022

J Anim Sci Technol

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5-Hydroxytryptamine (5-HT), a monoamine, as a local regulator in the mammary gland is a chemical signal produced by the mammary epithelium cell. In cows, studies have shown that 5-HT is associated with epithelial cell apoptosis during the degenerative phase of the mammary gland. However, studies in other tissues have shown that 5-HT can effectively promote cell viability. Whether 5-HT could have an effect on mammary cell viability in dairy cows is still unknown. The purpose of this study was to determine: (1) effect of 5-HT on the viability of bovine mammary epithelial cells and its related signaling pathways, (2) interaction between prolactin (PRL) and 5-HT on the cell viability. The bovine mammary alveolar cell-T (MAC-T) were cultured with different concentrations of 5-HT for 12, 24, 48 or 72 hours, and then were assayed using cell counting kit-8, polymerase chain reaction (PCR) and immunobloting. The results suggested that 20 μM 5-HT treatment for 12 or 24 h promote cell viability, which was mainly induced by the activation of 5-HT receptor (5-HTR) 1B and 4, because the increase caused by 5-HT vanished when 5-HTR 1B and 4 was blocked by SB224289 and SB204070. And protein expression of mammalian target of rapamycin (mTOR), eukaryotic translation elongation factor 2 (eEF2), janus kinase 2 (JAK2) and signal transducer and activator of transcription 5 (STAT5) were decreased after blocking 5-HT 1B and 4 receptors. When MAC-T cells were treated with 5-HT and PRL simultaneously for 24 h, both the cell viability and the level of mTOR protein were significantly higher than that cultured with 5-HT or PRL alone. In conclusion, our study suggested that 5-HT promotes the viability of MAC-T cells by 5-HTR 1B and/or 4. Furthermore, there is a reciprocal relationship between PRL and 5-HT.

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Investigations of Piperazine Derivatives as Intestinal Permeation Enhancers in Isolated Rat Intestinal Tissue Mucosae

Cited by 10 publications

References 53 publications

Development and characterisation of ibuprofen-loaded nanoemulsion with enhanced oral bioavailability

Development and characterisation of ibuprofen-loaded nanoemulsion with enhanced oral bioavailability

Long‐term daily oral administration of intestinal permeation enhancers is safe and effective in mice

Effect of serotonin on the cell viability of the bovine mammary alveolar cell-T (MAC-T) cell line

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