Optimizing Caco-2 cell monolayers to increase throughput in drug intestinal absorption analysis

Markowska, Maria; Oberle, Rebecca L.; Juzwin, Steve; Hsu, Cheng‐Pang; Gryszkiewicz, Margaret; Streeter, Anthony J.

doi:10.1016/s1056-8719(01)00161-7

Cited by 81 publications

(55 citation statements)

References 14 publications

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“…1. Effect of inclusion of amino acid and peptide transporter substrates on the in vitro-in vivo correlations of Caco-2 and human intestinal permeability measurements for eight studies (29)(30)(31)(32)(33)(34)(35)(36), where Caco-2 permeability measurements were available for at least 6 drugs, including metoprolol, of the 30 drugs with available human intestinal permeability measurements. The total number of compounds in each correlation range from 6 to 22, with the average being 11 correlations (Fig.…”

Section: Identifying Compounds For Which Caco-2 May Poorly Predict Humentioning

confidence: 99%

“…To help understand the impact of selecting Caco-2 permeability data from multiple sources to develop an in silico model, Fig. 2 illustrates the degree of variability in Caco-2 permeability measurements for 20 out of 30 drugs, that is those drugs for which both human intestinal permeability rate measurements are available (4) and multiple sources report their Caco-2 permeability measurements (8,20,(29)(30)(31)(32)(33)(34)(35)(36)79). Permeability values for each compound were included if metoprolol had also been studied in the Caco-2 evaluation to determine if the observed interlaboratory variability could be mitigated when the measurements were normalized to a reference standard.…”

Section: The Need For Larger Single-source Caco-2 Permeability Datasetsmentioning

confidence: 99%

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Drug Discovery and Regulatory Considerations for Improving In Silico and In Vitro Predictions that Use Caco-2 as a Surrogate for Human Intestinal Permeability Measurements

Larregieu

Benet

2013

AAPS J

129

119

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ABSTRACT. There is a growing need for highly accurate in silico and in vitro predictive models to facilitate drug discovery and development. Results from in vitro permeation studies across the Caco-2 cell monolayer are commonly used for drug permeability screening in industry and are also accepted as a surrogate for human intestinal permeability measurements by the US FDA to support new drug applications. Countless studies carried out in this cell line with published permeability measurements have enabled the development of many in silico prediction models. We identify several common cases that illustrate how using Caco-2 permeability measurements in these in silico and in vitro predictive models will not correlate with human intestinal permeability and will further lead to inaccuracies in these models. We provide guidelines and recommendations for improving these models to more accurately predict clinically relevant information, thereby enhancing the drug discovery, development, and regulatory approval processes.

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Section: Identifying Compounds For Which Caco-2 May Poorly Predict Humentioning

confidence: 99%

Section: The Need For Larger Single-source Caco-2 Permeability Datasetsmentioning

confidence: 99%

Drug Discovery and Regulatory Considerations for Improving In Silico and In Vitro Predictions that Use Caco-2 as a Surrogate for Human Intestinal Permeability Measurements

Larregieu

Benet

2013

AAPS J

129

119

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“…The cultures were kept in an atmosphere of 95% air and 5% CO 2 at 37 o C, and were used for the permeability experiments 18～21 days after seeding, when displayed TEER values of 400～550 Ω cm 2 . TEER values of the Caco-2 cell monolayers were monitored every 2～3 days with a Millicell-Electrical Resistance System (Millipore Corp., Bedford, MA, USA) connected to a pair of chopstick electrodes (13,15,16) In vitro Caco-2 permeability assay For in vitro Caco-2 permeability assay, the method of Markowska et al (17) was used, which is widely used for measuring cell permeable properties of particles. To initiate the transport experiment, the culture media in the apical and the basolateral compartments were aspirated, and the cells were rinsed twice with pre-warmed Hank's balanced salt solution (HBSS) at pH 7.4.…”

Section: Transepithelial Electrical Resistance (Teer) Measurements Dumentioning

confidence: 99%

“…500 μL of samples were collected from basolateral chambers at 0, 1, 2, 3, 4 hr, and then were immediately analyzed by a spectrophotometric method. Transwells without seeded cells were run concurrently as a control to measure the permeation rate of zinc oxide particles (17,18).…”

Section: Transepithelial Electrical Resistance (Teer) Measurements Dumentioning

confidence: 99%

Effect of Particle Size of Zinc Oxides on Cytotoxicity and Cell Permeability in Caco-2 Cells

Chang¹,

Choi²,

Ko³

et al. 2011

JFN

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The cell permeability and cytotoxic effects of different-sized zinc oxide (ZnO) particles were investigated using a human colorectal adenocarcinoma cell line called Caco-2. Morphological observation by scanning electron microscopy revealed that three zinc oxides with different mean particle sizes (ZnO-1, 20 nm; ZnO-2, 90～200 nm; ZnO-3, 1～5 μm) tended to aggregate, particularly in the case of ZnO-1. When cytotoxicities of all three sizes of zinc oxide particles were measured at concentration ranges of 1～1000 μg/mL, significant decreases in cell viability were observed at concentrations of 50 μg/mL and higher. Among the three zinc oxides, ZnO-1 showed the lowest viability at 50 μg/mL in Caco-2 cells, followed by ZnO-2 and ZnO-3. The permeate concentration of ZnO-1 from the apical to the basolateral side in the Caco-2 model system after four hours was about three-fold higher than that of either ZnO-2 or ZnO-3. These results demonstrated that ZnO-1, with a 20 nm mean particle size, had poorer viability and better permeability in Caco-2 cells than ZnO-2 and ZnO-3.

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“…At the end of the permeability experiments, 200 µL of fluorescein 1 mg/mL in phosphate-buffered saline was added to each apical chamber and 400 µL of phosphate-buffered saline was added to each basolateral chamber. [17][18][19] After one hour of incubation at 37°C , the fluorescein content in the basolateral medium was determined by HPLC, as previously described.…”

Section: Permeability Testing Conditionsmentioning

confidence: 99%

Development and characterization of a new oral dapsone nanoemulsion system: permeability and in silico bioavailability studies

Monteiro¹,

Lione²,

Carmo³

et al. 2012

IJN

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Background: Dapsone is described as being active against Mycobacterium leprae, hence its role in the treatment of leprosy and related pathologies. Despite its therapeutic potential, the low solubility of dapsone in water results in low bioavailability and high microbial resistance. Nanoemulsions are pharmaceutical delivery systems derived from micellar solutions with a good capacity for improving absorption. The aim of this work was to develop and compare the permeability of a series of dapsone nanoemulsions in Caco-2 cell culture against that of effective permeability in the human body simulated using Gastroplus TM software. Methods and results:The release profiles of the dapsone nanoemulsions using different combinations of surfactants and cosolvent showed a higher dissolution rate in simulated gastric and enteric fluid than did the dispersed dapsone powder. The drug release kinetics were consistent with a Higuchi model. Conclusion: This comparison of dapsone permeability in Caco-2 cells with effective permeability in the human body simulated by Gastroplus showed a good correlation and indicates potential improvement in the biodisponibility of dapsone using this new system.

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Optimizing Caco-2 cell monolayers to increase throughput in drug intestinal absorption analysis

Cited by 81 publications

References 14 publications

Drug Discovery and Regulatory Considerations for Improving In Silico and In Vitro Predictions that Use Caco-2 as a Surrogate for Human Intestinal Permeability Measurements

Drug Discovery and Regulatory Considerations for Improving In Silico and In Vitro Predictions that Use Caco-2 as a Surrogate for Human Intestinal Permeability Measurements

Effect of Particle Size of Zinc Oxides on Cytotoxicity and Cell Permeability in Caco-2 Cells

Development and characterization of a new oral dapsone nanoemulsion system: permeability and in silico bioavailability studies

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