Caco-2 cell monolayers as a model for drug transport across the intestinal mucosa.
ABSTRACT Human colon adenocarcinoma (Caco-2) cells, when grown on semipermeable filters, spontaneously differentiate in culture to form confluent monolayers which both structurally and functionally resemble the small intestinal epithelium. Because of this property they show promise as a simple, in vitro model for the study of drug absorption and metabolism during absorption in the intestinal mucosa. In the present study, the transport of several model solutes across Caco-2 cell monolayers grown in the Transwell diffusion cell system was examined. Maximum transport rates were found for the actively transported substance glucose and the lipophilic solutes testosterone and salicyclic acid. Slower rates were observed for urea, hippurate, and saliylate anions and were correlated with the apparent partition coefficient of the solute. These results are similar to what is found with the same compounds in other, in vivo absorption model systems. It is concluded that the Caco-2 cell system may give useful predictions concerning the oral absorption potential of new drug substances.
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ABSTRACT: Total flavones of Hippophae rhamnoides L. (TFH) are extracted from the widely distributed thorny bush Sea buckthorn (Hippophae rhamnoides L.). Isorhamnetin (IS) is one of the representative ingredients in TFH. In this study, the absorption properties of IS in TFH and its pure form were compared through transepithelial transport and cellular uptake experiments in a Caco-2 cell model. Our results show that the absorption properties of IS in TFH and its pure form were remarkably different: (1) Both PappAB and PappBA of IS in TFH were dramatically increased compared with those of IS pure form; consequently, its Pratio was 2.3-fold higher than that of IS; (2) Both the accumulation and efflux of IS in TFH were significantly enhanced compared with the single compound. One likely reason for these differences is that the multiple components in TFH significantly down regulated the mRNA expression level of MRP2, which lead to a decrease in the protein level of MRP2, based on western blotting and RT-PCR assays. This study highlights the significant differences in the absorption properties of flavonoid components in different forms and the potential multi-component interactions in TFH. Copyright © 2015. Published by Elsevier B.V.European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences 03/2015; 73. DOI:10.1016/j.ejps.2015.03.008 · 3.01 Impact Factor
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ABSTRACT: Preformulation measurements are used to estimate the fraction absorbed in vivo for orally administered compounds and thereby allow an early evaluation of the need for enabling formulations. As part of the Oral Biopharmaceutical Tools (OrBiTo) project, this review provides a summary of the pharmaceutical profiling methods available, with focus on in silico and in vitro models typically used to forecast active pharmaceutical ingredient's (APIs) in vivo performance after oral administration. An overview of the composition of human, animal and simulated gastrointestinal (GI) fluids is provided and state-of-the art methodologies to study API properties impacting on oral absorption are reviewed. Assays performed during early development, i.e. physicochemical characterization, dissolution profiles under physiological conditions, permeability assays and the impact of excipients on these properties are discussed in detail and future demands on pharmaceutical profiling are identified. It is expected that innovative computational and experimental methods that better describe molecular processes involved in vivo during dissolution and absorption of APIs will be developed in the OrBiTo. These methods will when successful provide early insights into successful pathways (medicinal chemistry or formulation strategy) and are anticipated to increase the number of new APIs with good oral absorption being discovered.European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences 11/2013; 57. DOI:10.1016/j.ejps.2013.10.015 · 3.01 Impact Factor
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ABSTRACT: Beauvericin (BEA) is a cyclohexadepsipeptide mycotoxin which has insecticidal properties and produces cytotoxic effects in mammalian cells. Fusaproliferin (FUS) is a mycotoxin that has toxic activity against brine shrimp, insect cells, and teratogenic effects on chicken embryos. The aim of this study was to determine the cytotoxicity of BEA and FUS in human epithelial colorectal adenocarcinoma HT-29 and Caco-2 cells, the transepithelial transport and the bioavailability using Caco-2 cells as a simulated in vitro gastrointestinal model of the human intestinal epithelium. The inhibitory concentration (IC(50)) evidenced by BEA in the Caco-2 cells was 24.6 and 12.7 μM at 24 and 48 h exposure, respectively, whereas the IC(50) values evidenced in HT-29 cells were 15.0 and 9.7 μM, respectively. FUS was cytotoxic, but no IC(50) data were observed in the range of concentration tested. BEA bioavailability was variable from 50.1% to 54.3%, whereas FUS presented a bioavailability variable from 80.2% to 83.2%. Results obtained demonstrated a potential risk for human health.Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association 04/2012; 50(7):2356-61. DOI:10.1016/j.fct.2012.04.030 · 2.61 Impact Factor