Passive Diffusion of Weak Organic Electrolytes across Caco‐2 Cell Monolayers: Uncoupling the Contributions of Hydrodynamic, Transcellular, and Paracellular Barriers

Adson, Anthony; Burton, Philip S.; Raub, Thomas J.; Barsuhn, Craig L.; Audus, Kenneth L.; Ho, Norman F.H.

doi:10.1002/jps.2600841011

Cited by 143 publications

(166 citation statements)

References 32 publications

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“…It has been claimed that slight shaking using plate shakers cannot reduce the thickness of the UWL sufficiently to match the in vivo situation , but there are other reports showing that already at 150 rpm the thickness can be considerably reduced down to 220 µm when using an orbital shaker (Adson et al, 1995). In that study the amount of testosterone that entered the acceptor chamber was clearly increased when increasing the shaking from 25 rpm to 50 or 100 rpm.…”

Section: Resultsmentioning

confidence: 80%

“…3.1.1 Influence of agitation on the permeability of drugs and the physical stability of the barrier In the most used permeability models, the Caco-2 model and the PAMPA model, the adherent "fixed" layer of water, the so-called unstirred water layer (UWL) has been found to significantly influence the permeability values (Adson et al, 1995;Kansy et al, 2004;Karlsson and Artursson, 1991). Especially if drug diffusion in water is slow, i.e.…”

Section: Resultsmentioning

confidence: 99%

“…Means to decrease or even minimize this effect have involved e.g. shaking or stirring of the permeation assay setup (Adson et al, 1995;Avdeef et al, 2004;Karlsson and Artursson, 1991). The phospholipid vesicle based method has so far been run without agitation, so the aim of this part of the study was therefore to investigate the effect of agitation.…”

Section: Resultsmentioning

confidence: 99%

“…It has been shown in both Caco-2 and PAMPA models that agitation during the permeability experiments can decrease the UWL and thereby increase the apparent permeability of lipophilic drug compounds (Adson et al, 1995;Avdeef et al, 2004;Karlsson and Artursson, 1991). It has been claimed that slight shaking using plate shakers cannot reduce the thickness of the UWL sufficiently to match the in vivo situation , but there are other reports showing that already at 150 rpm the thickness can be considerably reduced down to 220 µm when using an orbital shaker (Adson et al, 1995).…”

Section: Resultsmentioning

confidence: 99%

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Drug permeability across a phospholipid vesicle based barrier: 3. Characterization of drug–membrane interactions and the effect of agitation on the barrier integrity and on the permeability

Flaten¹,

Skar²,

Luthman³

et al. 2007

European Journal of Pharmaceutical Sciences

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Recently we reported on the development and structural characterization of a phospholipid vesicle based barrier useful for medium throughput screening of passive drug permeability.Here, we investigate the physical and functional integrity of the phospholipid vesicle based barriers to agitation by stirring or shaking, and whether agitation affects drug permeability of sulpiride, metoprolol and testosterone. In addition, three drugs (caffeine, naproxen and sulphasalazine) which were shown in a previous study to affect the electrical resistance of the barriers, were investigated for their influence on the permeability of a simultaneously applied hydrophilic marker (calcein), and on the thermotropic phase transition of the phospholipid bilayers using differential scanning calorimetry (DSC).Electrical resistance measurements indicated that the barriers should withstand shaking speeds up to 150 rpm without losing their integrity, but significant release of phospholipids from the membrane barriers to the donor and acceptor chambers was observed under agitation ≥150 rpm. When using agitation up to 100 rpm no increase in permeability was observed for sulpiride, metoprolol and testosterone. The phospholipid vesicle-based barrier thus differ from other permeability models in that agitation does not lead to an increase in permeability, not even for highly lipophilic drugs such as testosterone. This is explained by the different morphology of the vesicle-based barrier which is containing a 100 µm thick layer of mostly aqueous compartments immobilised within a matrix of phospholipids vesicles.Sulphasalazine and naproxen were shown to decrease the electrical resistance and increase the permeability of the hydrophilic marker calcein. The DSC experiments showed that these two drugs probably interact with the head groups of the phospholipids. In contrast, caffeine gave an increase in electrical resistance and a decrease in permeability of calcein. From the DSC experiments no signs of interaction of caffeine with the phospholipid bilayer could be observed.3

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Section: Resultsmentioning

confidence: 80%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 2 more Smart Citations

Drug permeability across a phospholipid vesicle based barrier: 3. Characterization of drug–membrane interactions and the effect of agitation on the barrier integrity and on the permeability

Flaten¹,

Skar²,

Luthman³

et al. 2007

European Journal of Pharmaceutical Sciences

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“…The binding parameters from the single cell uptake study (Table 1) (1997) 76(7) (Adson et al, 1994(Adson et al, , 1995. The latter have been investigated as models for endothelial or epithelial absorption barriers but, being only one cell thick, do not include the heterogeneous microenvironments that arise as a result of limiting transport of nutrients, oxygen and waste products in the extravascular compartment of tumours.…”

Section: Diffusion Of [3h]dapa Through V79-171 B MMmentioning

confidence: 99%

An experimental and mathematical model for the extravascular transport of a DNA intercalator in tumours

Hicks

Ohms²,

Zijl³

et al. 1997

Br J Cancer

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9-[3-(N,N-dimethylamino)propylamino]acridine (DAPA) was dramatically slower than urea. Modelling this over the first 5 h gave a DMM of 1.3 x 10-cm2 s-1, but over longer times the kinetics was not consistent with simple diffusion. Flux of DAPA was markedly increased in the presence of 50 mm ammonium chloride, indicating that sequestration in acidic endosomes is a major impediment to flux. Accumulation in cytoplasmic vesicles was confirmed by fluorescence microscopy. The DAPA flux kinetics, with and without ammonium chloride, was well fitted by a reaction-diffusion model with reversible cellular uptake (modelled as binding), using uptake parameters determined in separate experiments with V79-171 b single-cell suspensions. This study demonstrates the utility of the MM model for determining extravascular transport parameters, and indicates that much of the impediment to diffusion of basic DNA intercalators in tumour tissue may arise from lysosomal sequestration rather than DNA binding.

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Cell Cultures in Drug Discovery: An Industrial Perspective

Ungell

Karlsson

2003

Methods and Principles in Medicinal Chemistry

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Passive Diffusion of Weak Organic Electrolytes across Caco‐2 Cell Monolayers: Uncoupling the Contributions of Hydrodynamic, Transcellular, and Paracellular Barriers

Cited by 143 publications

References 32 publications

Drug permeability across a phospholipid vesicle based barrier: 3. Characterization of drug–membrane interactions and the effect of agitation on the barrier integrity and on the permeability

Drug permeability across a phospholipid vesicle based barrier: 3. Characterization of drug–membrane interactions and the effect of agitation on the barrier integrity and on the permeability

An experimental and mathematical model for the extravascular transport of a DNA intercalator in tumours

Cell Cultures in Drug Discovery: An Industrial Perspective

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