Transport and permeability properties of human Caco-2 cells: An in vitro model of the intestinal epithelial cell barrier

Wilson, Glynn; Hassan, Ian F.; Dix, C. J.; Williamson, Ian; Shah, Rakhi B.; Mackay, Martin; Artursson, Per

doi:10.1016/0168-3659(90)90118-d

Cited by 198 publications

(102 citation statements)

References 19 publications

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“…As previously discussed (Audus et al, 1990), the selection of the cell line becomes particularly important to mimic successfully a biological barrier. Therefore, Caco-2 were used, since they exhibit the functional characteristics of cells of the lower small intestinal tract (Pinto et al, 1983;Wilson et al, 1990;Hidalgo & Borchardt, 1990a,b). The cells used by us showed a directed transport of taurocholate and phenylalanine and expressed a high activity of alakaline phosphatase at confluency.…”

Section: Discussionmentioning

confidence: 99%

Relevance of p‐glycoprotein for the enteral absorption of cyclosporin A: in vitro‐in vivo correlation

Fricker¹,

Drewe

Huwyler

et al. 1996

British J Pharmacology

207

134

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. The interaction of cyclosporin A (CyA) with p‐glycoprotein during intestinal uptake was investigated by a combination of in vitro experiments with human Caco‐2 cells and an intubation study in healthy volunteers. . CyA uptake into the cells was not saturable and exhibited only a low temperature sensitivity, suggesting passive diffusion. When the permeation of CyA across Caco‐2 monolayers from the apical to the basolateral side was determined, overall transport had an apparently saturable component up to a concentration of 1 μm. At higher concentrations permeation increased over‐proportionally. Calculation of the kinetic parameters of apical to basolateral permeation suggested a diffusional process with a KD of 0.5 μl min−1 per filter, which was overlayed by an active system in basolateral to apical direction with a KM of 3.8 μm and a Jmax of 6.5 picomol min−1 per filter. . CyA permeation was significantly higher when the drug was given from the basolateral side as compared to the permeation from the apical side. Apical to basolateral transport of CyA was increased in the presence of vinblastine, daunomcyin and a non‐immunosuppressive CyA‐derivative. All compounds inhibit p‐glycoprotein‐mediated transport processes. Basolateral to apical permeation of CyA showed a dose‐dependent decrease in the presence of vinblastine. Permeation of daunomycin across Caco‐2 cell monolayers was also higher from the basolateral to the apical side than vice versa. Basolateral to apical permeation was decreased in the presence of SDZ PSC 833 and cyclosporin A. . Western blot analysis of Caco‐2 cells with the monoclonal antibody C219 confirmed the presence of p‐glycoprotein in the used cell system. . When the absorption of CyA in the gastrointestinal (G***I)‐tract of healthy volunteers was determined, a remarkable decrease of the plasma AUC could be observed dependent on the location of absorption in the rank order stomach > jejunum/ileum > colon. The decrease in absorption exhibited a marked correlation (r = 0.994) to the expression of mRNA for p‐glycoprotein over the G**I‐tract (stomach < jejunum < colon). . All data provide evidence that CyA is a substrate of p‐glycoprotein in the G***I‐tract, which might explain the local differences and the high variability in cyclosporin absorption found in vivo.

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Section: Discussionmentioning

confidence: 99%

Relevance of p‐glycoprotein for the enteral absorption of cyclosporin A: in vitro‐in vivo correlation

Fricker¹,

Drewe

Huwyler

et al. 1996

British J Pharmacology

207

134

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“…Hidalgo & Borchardt, 1990;Hu & Borchardt, 1992;Nicklin et al, 1992) and vitamin B-12 , as well as a variety of drugs (e.g. Artursson, 1990;Hu & Borchardt, 1990;Wilson et al, 1990;Conradi et al, 1991;Inui et al, 1992;Ranaldi et al, 1992). A good correlation between drug absorption in Caco-2 monolayers in man has been established (Artursson & Karlsson, 1991).…”

Section: Introductionmentioning

confidence: 99%

Transport of celiprolol across human intestinal epithelial (Caco‐2) cells: mediation of secretion by multiple transporters including P‐glycoprotein

Karlsson

Kuo²,

Ziemniak³

et al. 1993

British J Pharmacology

170

100

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1 The transepithelial transport of the P-adrenoceptor blocking drug, celiprolol, was investigated in monolayers of the well differentiated human intestinal epithelial cell line, Caco-2.2 The basal-to-apical transport (secretion) of ['4C]-celiprolol (50 jLM) was 5 times higher than apical-tobasal transport (absorption). In the presence of an excess (5 mM) of unlabelled celiprolol the basal-toapical transport was reduced by more than 80%, whereas the apical-to-basal transport remained unchanged. 3 Net celiprolol secretion obtained in the concentration range 0.01 to 5 mM displayed saturable kinetics with an apparent Km of 1.00 ± 0.23 mm and Vm,, of 113 ± 11 pmol/106 cells min-'. These results are consistent with saturable active secretion and provide an explanation for the dose-dependent bioavailability of celiprolol. 4 The secretion of celiprolol was sensitive to pH, and decreased in the absence of sodium and in the presence of ouabain, suggesting that transport was coupled to proton and sodium gradients. 5 The secretion of celiprolol was inhibited by substrates for P-glycoprotein (vinblastine, verapamil and nifedipine) and either inhibited or stimulated by typical substrates for the renal organic cation-H+ exchanger (cimetidine, N'-methylnicotinamide, tetraethylammonium and choline), suggesting that there are at least two distinct transport systems.6 The secretion of celiprolol was also inhibited by other P-adrenoceptor blocking drugs (acebutolol, atenolol, metoprolol, pafenolol and propranolol) and by the diuretics, acetazolamide, chlorthalidone and hydrochlorothiazide, suggesting that the clinically observed effect of chlorthalidone on the bioavailability of celiprolol occurs at the level of the intestinal epithelium.

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“…The Caco-2 cell monolayer has been well established as an in vitro model for the study of oral drug absorption. 23 The differentiated cell monolayer has tight junctions and drug efflux transporters and thus resembles the normal intestinal epithelium as a drug absorption barrier. 24,25 A desirable oral drug delivery system should have the ability to modulate the intestinal absorptive barrier so as to transport drugs across and promote absorption, in addition to being minimally toxic to the intestinal barrier.…”

Section: Introductionmentioning

confidence: 99%

Functionalized carbon nanomaterials: exploring the interactions with Caco-2 cells for potential oral drug delivery

Coyuco¹,

Liu²,

Tan³

et al. 2011

IJN

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Although carbon nanomaterials (CNMs) have been increasingly studied for their biomedical applications, there is limited research on these novel materials for oral drug delivery. As such, this study aimed to explore the potential of CNMs in oral drug delivery, and the objectives were to evaluate CNM cytotoxicity and their abilities to modulate paracellular transport and the P-glycoprotein (P-gp) efflux pump. Three types of functionalized CNMs were studied, including polyhydroxy small-gap fullerenes (OH-fullerenes), carboxylic acid functionalized single-walled carbon nanotubes ( f SWCNT-COOH) and poly(ethylene glycol) functionalized single-walled carbon nanotubes ( f SWCNT-PEG), using the well-established Caco-2 cell monolayer to represent the intestinal epithelium. All three CNMs had minimum cytotoxicity on Caco-2 cells, as demonstrated through lactose dehydrogenase release and 3-(4,5-dimethyliazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Of the three CNMs, f SWCNT-COOH significantly reduced transepithelial electrical resistance and enhanced transport of Lucifer Yellow across the Caco-2 monolayer. Confocal fluorescence microscopy showed that f SWCNT-COOH treated cells had the highest perturbation in the distribution of ZO-1, a protein marker of tight junction, suggesting that f SWCNT-COOH could enhance paracellular permeability via disruption of tight junctions. This modulating effect of f SWCNT-COOH can be reversed over time. Furthermore, cellular accumulation of the P-gp substrate, rhodamine-123, was significantly increased in cells treated with f SWCNT-COOH, suggestive of P-gp inhibition. Of note, f SWCNT-PEG could increase rhodamine-123 accumulation without modifying the tight junction. Collectively, these results suggest that the functionalized CNMs could be useful as modulators for oral drug delivery, and the differential effects on the intestinal epithelium imparted by different types of CNMs would create unique opportunities for drug-specific oral delivery applications.

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Transport and permeability properties of human Caco-2 cells: An in vitro model of the intestinal epithelial cell barrier

Cited by 198 publications

References 19 publications

Relevance of p‐glycoprotein for the enteral absorption of cyclosporin A: in vitro‐in vivo correlation

Relevance of p‐glycoprotein for the enteral absorption of cyclosporin A: in vitro‐in vivo correlation

Transport of celiprolol across human intestinal epithelial (Caco‐2) cells: mediation of secretion by multiple transporters including P‐glycoprotein

Functionalized carbon nanomaterials: exploring the interactions with Caco-2 cells for potential oral drug delivery

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