Effect of chitosan glutamate, carbomer 974P, and EDTA on the in vitro Caco-2 permeability and oral pharmacokinetic profile of acyclovir in rats

Merzlikine, Alexei G.; Rotter, Charles J.; Rago, Brian; Poe, Julie; Christoffersen, Curt; Thomas, V. Hayden; Troutman, Matthew D.; El‐Kattan, Ayman

doi:10.1080/03639040902774156

Cited by 22 publications

(19 citation statements)

References 23 publications

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“…All products were dispersed in 100 mL water and administered with another 150 mL, resulting in a total volume of 250 mL water. Start concentrations of 1.6 g/L (0.16%) and 4.0 g/L (0.4%) chitosan HCl were thus obtained, in line with those described in literature (0.1%–0.5%) (15,16). The maximum chitosan dose was limited to 1 g in view of the practical feasibility of oral intake of the quantity as a single dose and the related limited relevance of higher quantities as a potential excipient in an actual solid oral dosage form.…”

Section: Methodssupporting

confidence: 90%

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The Influence of Chitosan on the Oral Bioavailability of Acyclovir—a Comparative Bioavailability Study in Humans

et al. 2015

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PurposeThe effects of chitosan hydrochloride on the oral absorption of acyclovir in humans were studied to confirm the absorption enhancing effects reported for in vitro and rat studies, respectively.MethodsA controlled, open-label, randomized, 3-phase study was conducted in 12 healthy human volunteers. Zovirax 200 mg dispersible tablets co-administered with doses of 400 and 1000 mg chitosan HCl were compared with Zovirax only.ResultsThe expected increased absorption of acyclovir was not observed. On the contrary, mean area under the plasma concentration-time curve (AUC0-12 h) and maximal plasma concentration (Cmax) decreased following concomitant chitosan intake (1402 versus 1017 and 982.0 ng∙h/ml and 373 versus 208 and 235 ng/ml, respectively). In addition, Tmax increased significantly in presence of 1000 mg of chitosan from 1 to 2 h.ConclusionsThe results of this study in human volunteers did not confirm an absorption enhancing effect of chitosan. Reference values were comparable to literature data, whereas addition of chitosan resulted in significant opposite effects on Cmax, Tmax and AUC. Additional studies are needed to investigate the cause of the discrepancy. The observed variability and complex potential interactions may complicate the use of chitosan HCl in oral pharmaceutical formulations.Electronic supplementary materialThe online version of this article (doi:10.1007/s11095-014-1613-y) contains supplementary material, which is available to authorized users.

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Section: Methodssupporting

confidence: 90%

“…The extract was centrifuged at 14000 rpm for 10 min at −5°C and the concentration of acyclovir was determined by LC-MS/MS using a sample injection volume of 10 μl. The bioanalytical method was modified from previously reported methods (16,19,20). Validation data are included as supplementary material.…”

Section: Methodsmentioning

confidence: 99%

The Influence of Chitosan on the Oral Bioavailability of Acyclovir—a Comparative Bioavailability Study in Humans

et al. 2015

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“…Typically, these rely on addition of chemicals [16–20] or co-culture with other cell types [12,21–24]. Various three-dimensional (3D) drug screening models have also been developed, including organoid structures derived from primary tissue [25,26] and micro-fluidic, organ-on-a-chip devices [27].…”

Section: Introductionmentioning

confidence: 99%

Improvement of paracellular transport in the Caco-2 drug screening model using protein-engineered substrates

et al. 2017

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The Caco-2 assay has achieved wide popularity among pharmaceutical companies in the past two decades as an in vitro method for estimation of in vivo oral bioavailability of pharmaceutical compounds during preclinical characterization. Despite its popularity, this assay suffers from a severe under-prediction of the transport of drugs which are absorbed paracellularly, that is, which pass through the cell-cell tight junctions of the absorptive cells of the small intestine. Here, we propose that simply replacing the collagen I matrix employed in the standard Caco-2 assay with an engineered matrix, we can control cell morphology and hence regulate the cell-cell junctions that dictate paracellular transport. Specifically, we use a biomimetic engineered extracellular matrix (eECM) that contains modular protein domains derived from two ECM proteins found in the small intestine, fibronectin and elastin. This eECM allows us to independently tune the density of cell-adhesive RGD ligands presented to Caco-2 cells as well as the mechanical stiffness of the eECM. We observe that lower amounts of RGD ligand presentation as well as decreased matrix stiffness results in Caco-2 morphologies that more closely resemble primary small intestinal epithelial cells than Caco-2 cells cultured on collagen. Additionally, these matrices result in Caco-2 monolayers with decreased recruitment of actin to the apical junctional complex and increased expression of claudin-2, a tight junction protein associated with higher paracellular permeability that is highly expressed throughout the small intestine. Consistent with these morphological differences, drugs known to be paracellularly transported in vivo exhibited significantly improved transport rates in this modified Caco-2 model. As expected, permeability of transcellularly transported drugs remained unaffected. Thus, we have demonstrated a method of improving the physiological accuracy of the Caco-2 assay that could be readily adopted by pharmaceutical companies without major changes to their current testing protocols.

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“…The culture conditions for growing Caco-2 cells were as described previously [29][30][31][32] . When comparing the permeability, each used at the same concentration (10 μM) and the samples taken at 0, 1, 2, 3 and 4 h after incubation.…”

Section: Cell Culture and Transport Experimentsmentioning

confidence: 99%

A novel drug–phospholipid complex loaded micelle for baohuoside I enhanced oral absorption:in vivoandin vivoevaluations

Jin

Zhang

Sun

et al. 2012

Drug Development and Industrial Pharmacy

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Baohuoside I is an effective anti-cancer drug currently used for a variety of cancers in vitro. Unfortunately, baohuoside I has a very poor solubility in both water and in organic solvents. Besides that, it is subject to significant efflux. This work therefore aimed at evaluating the ability of mixed micelles to solubilize baohuoside I, increase permeability and inhibit efflux of baohuoside I to promote oral absorption. A novel (TPGS-baohuoside I-phospholipid complex) mixed micelles was formed by phospholipid complex and TPGS to increase the solubility, enhance permeability, and inhibit efflux of baohuoside I. Micelle formation was confirmed by differential scanning calorimetry and transmission electron microscopy. The average diameters and efflux ratio of mixed micelles decreased as the ratio of TPGS increased with a respective increase in solubility of baohuoside I. Nevertheless, a slow release of baohuoside I from loaded micelles was noted. The results showed that at a 1:9 ratio for baohuoside I-phospholipid complex: TPGS in mixed micelles, solubility of baohuoside I increased up to 88 fold while the efflux ratio decreased by 85%. Their smaller size and higher zeta potential values indicated that mixed micelles would be easily absorbed and more stable. The relative bioavailability of the micelles (AUC(0-∞)) compared with baohuoside I (AUC(0-∞)) was 533%, demonstrating great potential for clinical application. Hence, the novel micelles formed with phospholipid complex and TPGS considerably increased drug concentration in the media and enhanced absorption.

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Effect of chitosan glutamate, carbomer 974P, and EDTA on the in vitro Caco-2 permeability and oral pharmacokinetic profile of acyclovir in rats

Abstract: In conclusion, chitosan glutamate (1-3%) and chitosan glutamate (1%)/EDTA-Na2 (0.01%) are effective excipients to increase permeability of acyclovir across Caco-2 cell monolayers and the oral absorption in the rat in vivo.

Cited by 22 publications

References 23 publications

The Influence of Chitosan on the Oral Bioavailability of Acyclovir—a Comparative Bioavailability Study in Humans

The Influence of Chitosan on the Oral Bioavailability of Acyclovir—a Comparative Bioavailability Study in Humans

Improvement of paracellular transport in the Caco-2 drug screening model using protein-engineered substrates

A novel drug–phospholipid complex loaded micelle for baohuoside I enhanced oral absorption:in vivoandin vivoevaluations

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