Suitability of Isolated Rat Jejunum Model for Demonstration of Complete Absorption in Humans for BCS-Based Biowaiver Request

Peternel, Luka; Kristan, Katja; Petrushevska, Marija; Rižner, Tea Lanišnik; Legen, Igor

doi:10.1002/jps.23027

Cited by 22 publications

(25 citation statements)

References 82 publications

(51 reference statements)

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“…Isolated rat jejunal mucosae contain properties that map to the human jejunum. 39 These include mucus layers, extracellular matrix proteins, host enzyme levels, 47 supportive cells, and basement muscle layers. 50−52 Lacking mucus and supportive cells underlying the epithelial barrier, Caco-2 cell cultures may be sensitive to PAMAM dendrimer induced mannitol permeability enhancement compared to rat jejunal mucosae.…”

Section: Discussionmentioning

confidence: 99%

Transepithelial Transport of PAMAM Dendrimers across Isolated Rat Jejunal Mucosae in Ussing Chambers

Hubbard

Ghandehari²,

Brayden

2014

Biomacromolecules

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Oral delivery remains a challenge for poorly permeable hydrophilic macromolecules. Poly(amido amine) (PAMAM) dendrimers have shown potential for their possible oral delivery. Transepithelial transport of carboxyl-terminated G3.5 and amine-terminated G4 PAMAM dendrimers was assessed using isolated rat jejunal mucosae mounted in Ussing chambers. The 1 mM FITC-labeled dendrimers were added to the apical side of mucosae. Apparent permeability coefficients (Papp) from the apical to the basolateral side were significantly increased for FITC when conjugated to G3.5 PAMAM dendrimer compared to FITC alone. Minimal signs of toxicity were observed when mucosae were exposed to both dendrimers with respect to transepithelial electrical resistance changes, carbachol-induced short circuit current stimulation, and histological changes. [14C]-mannitol fluxes were not altered in the presence of 1 mM dendrimers, suggesting that the paracellular pathway was not affected at this concentration in this model. These results give insight into the mechanism of PAMAM dendrimer transepithelial rat jejunal transport, as well as toxicological considerations important for oral drug delivery.

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Section: Discussionmentioning

confidence: 99%

Transepithelial Transport of PAMAM Dendrimers across Isolated Rat Jejunal Mucosae in Ussing Chambers

Hubbard

Ghandehari²,

Brayden

2014

Biomacromolecules

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“…Merely limited jejunal permeability studies in humans have been conducted, likely due to the complexity and high costs of each procedure . More information is provided for intestinal perfusion studies and in‐vitro permeation studies by using animal intestinal tissues, mostly from rats . The most popular human intestinal permeability screening method has been Caco‐2 cell monolayers …”

Section: Introductionmentioning

confidence: 99%

“…[5] More information is provided for intestinal perfusion studies and in-vitro permeation studies by using animal intestinal tissues, mostly from rats. [6][7][8] The most popular human intestinal permeability screening method has been Caco-2 cell monolayers. [5] The Caco-2 cell line originates from human colorectal adenocarcinoma cells [9] and has been widely used in pharmaceutical research over last thirty years within absorption, distribution, metabolism and excretion studies as an invitro cell culture model of the intestinal mucosa.…”

Section: Introductionmentioning

confidence: 99%

Demonstrating suitability of the Caco-2 cell model for BCS-based biowaiver according to the recent FDA and ICH harmonised guidelines

Jarc

Novak

Hevir³

et al. 2019

Journal of Pharmacy and Pharmacology

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Objective According to the regulatory guidelines, one of the critical steps in using in‐vitro permeability methods for permeability classification is to demonstrate the suitability of the method. Here, suitability of the permeability method by using a monolayer of cultured epithelial cells was verified with different criteria. Methods Imaging with a transmission electron microscope was used for characterisation of the cells. Monolayer integrity was confirmed by transepithelial electrical resistance measurements and permeability of zero permeability marker compounds. Real‐time polymerase chain reaction was employed to evaluate expression levels of 84 known transporters. Samples for bidirectional permeability determination were quantified by ultra‐performance liquid chromatography. Key findings The Caco‐2 cells grow in an intact monolayer and morphologically resemble enterocytes. Genes of 84 known transporters were expressed at different levels; furthermore, expression was time depended. Functional expression of efflux transporter P‐glycoprotein was confirmed. We established a correlation between permeability coefficients of 21 tested drug substances ranging from low, moderate and high absorption with human fraction absorbed literature data (R2 = 0.84). Conclusions Assay standardisation assures the consistency of experimental data. Only such fully characterised model has the ability to accurately predict drug's intestinal permeability at the early stage of research or for the BCS‐based biowaiver application.

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“…Breast cancer is the most common cancer in women, with more than 1,300,000 cases and 450,000 deaths each year worldwide [1]. Despite considerable advances in early detection as well as therapeutic strategies with surgery, radiotherapy, and chemotherapy, the mortality rates in breast cancer patients have remained relatively unaffected over the span of three decades [2].…”

Section: Introductionmentioning

confidence: 99%

Dual Agent Loaded PLGA Nanoparticles Enhanced Antitumor Activity in a Multidrug-Resistant Breast Tumor Xenograft Model

Chen

Zheng

Fang

et al. 2014

IJMS

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Multidrug-resistant breast cancers have limited and ineffective clinical treatment options. This study aimed to develop PLGA nanoparticles containing a synergistic combination of vincristine and verapamil to achieve less toxicity and enhanced efficacy on multidrug-resistant breast cancers. The 1:250 molar ratio of VCR/VRP showed strong synergism with the reversal index of approximately 130 in the multidrug-resistant MCF-7/ADR cells compared to drug-sensitive MCF-7 cells. The lyophilized nanoparticles could get dispersed quickly with the similar size distribution, zeta potential and encapsulation efficiency to the pre-lyophilized nanoparticles suspension, and maintain the synergistic in vitro release ratio of drugs. The co-encapsulated nanoparticle formulation had lower toxicity than free vincristine/verapamil combinations according to the acute-toxicity test. Furthermore, the most effective tumor growth inhibition in the MCF-7/ADR human breast tumor xenograft was observed in the co-delivery nanoparticle formulation group in comparison with saline control, free vincristine, free vincristine/verapamil combinations and single-drug nanoparticle combinations. All the data demonstrated that PLGANPs simultaneously loaded with chemotherapeutic drug and chemosensitizer might be one of the most potential formulations in the treatment of multidrug-resistant breast cancer in clinic.

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Suitability of Isolated Rat Jejunum Model for Demonstration of Complete Absorption in Humans for BCS-Based Biowaiver Request

Cited by 22 publications

References 82 publications

Transepithelial Transport of PAMAM Dendrimers across Isolated Rat Jejunal Mucosae in Ussing Chambers

Transepithelial Transport of PAMAM Dendrimers across Isolated Rat Jejunal Mucosae in Ussing Chambers

Demonstrating suitability of the Caco-2 cell model for BCS-based biowaiver according to the recent FDA and ICH harmonised guidelines

Dual Agent Loaded PLGA Nanoparticles Enhanced Antitumor Activity in a Multidrug-Resistant Breast Tumor Xenograft Model

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