Active secretion and enterocytic drug metabolism barriers to drug absorption

Wacher, Vincent J.; Salphati, Laurent; Benet, Leslie Z.

doi:10.1016/0169-409x(95)00127-s

Cited by 232 publications

(197 citation statements)

References 66 publications

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“…multi-drug resistance proteins like the P-glycoprotein) in the intestinal epithelium (Burton et al 1997 ). To study and determine interactions between bioactive molecules during transport across the intestinal epithelium (Wacher et al 1996 ).…”

Section: Applicationsmentioning

confidence: 99%

Caco-2 Cell Line

Lea

2015

The Impact of Food Bioactives on Health

208

160

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The human epithelial cell line Caco-2 has been widely used as a model of the intestinal epithelial barrier. The Caco-2 cell line is originally derived from a colon carcinoma. However, one of its most advantageous properties is its ability to spontaneously differentiate into a monolayer of cells with many properties typical of absorptive enterocytes with brush border layer as found in the small intestine. The Caco-2 cell line is heterogeneous and contains cells with slightly different properties. Thus, cultivation conditions can be expected to select for the growth of subpopulations of cells resulting in a cellular model system with properties that may differ from the original cell line. Accordingly, results obtained under similar experimental conditions in different laboratories may not be directly comparable. Due to this, a variety of cloned Caco-2 cell lines has been established, and described in the literature. This chapter will however, focus on describing how to handle and cultivate the original Caco-2 cell line as obtained from cell culture collections like American Type Culture Collection and the European Collection of Cell Cultures. Detailed protocols for handling the Caco-2 cells in the laboratory are provided. Furthermore, in Chap. 9 general protocols for measuring barrier function by transepithelial resistance (TEER), and monolayer integrity by Lucifer Yellow fl ux are described. Proper testing of the cell monolayer is absolutely critical in exploiting Caco-2 cells to measure interaction, uptake and cellular transport of drugs and food components.

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Section: Applicationsmentioning

confidence: 99%

Caco-2 Cell Line

Lea

2015

The Impact of Food Bioactives on Health

208

160

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“…Thus far, however, reports on the low oral bioavailability of paclitaxel in mice have discouraged the development of an oral formulation (Eiseman et al, 1994;Fujita et al, 1994). Recent experiments with mdrla P-glycoprotein-deficient mice have demonstrated that this poor uptake of orally administered paclitaxel results mainly from the presence of P-glycoprotein in the intestines (Sparreboom et al, 1997), which is supported by in vitro experiments (Wacher et al, 1996). P-glycoprotein is a transmembrane protein that is present in many normal tissues (Croop et al, 1989;Teeter et al, 1990;Schinkel et al, 1994).…”

mentioning

confidence: 90%

Enhanced oral bioavailability of paclitaxel in mice treated with the P-glycoprotein blocker SDZ PSC 833

Asperen

Tellingen²,

Sparreboom³

et al. 1997

Br J Cancer

177

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“…In vitro investigations with human liver microsomes have shown that cytochrome P450 3A plays a predominant role in the metabolism of LVR. High first pass metabolism can also occur due to intestinal efflux which can lead to increased exposure time to metabolizing enzymes (Wacher et al, 1995;Wacher et al, 2001;Katragadda et al, 2005). We have hypothesized that the low oral bioavailability of LVR and possibly limited brain penetration could be in part due to efflux of LVR by several efflux pumps such as Pglycoprotein (P-gp), multidrug-resistance related proteins (MRPs) and breast cancer resistance protein (BCRP) present on intestinal epithelial and blood capillary endothelial cells.…”

Section: Introductionmentioning

confidence: 99%

Both P-gp and MRP2 mediate transport of Lopinavir, a protease inhibitor

Agarwal

Pal

Mitra

2007

International Journal of Pharmaceutics

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Polarized epithelial non-human (canine) cell lines stably transfected with human or murine complementary DNA (cDNA) encoding for various efflux transporters (P-gp/MDR1, MRP1, MRP2, and Bcrp1) were used to study transepithelial transport of Lopinavir (LVR) and compare results with the MDCKII-Wild type cells. These transmembrane proteins cause multidrug resistance by decreasing the total intracellular accumulation of drugs. Lopinavir efflux was directional and was completely inhibited by MK-571, a selective MRP family inhibitor in the MDCKII-MRP2 cell line. Similarly, LVR efflux was also inhibited by P-gp inhibitors P-gp 4008 and GF120918 in the MDCKII-MDR1 cell line. The efflux ratios (Efflux rate/ Influx rate) of LVR in the absence of any efflux inhibitors in the MDCK-Wild type, MDCKII-MDR1, MDCKII-MRP1 and MDCKII-MRP2 cell monolayers were 1.32, 4.91, 1.26 and 2.89 respectively. The MDCKII-MDR1 and MDCKII-MRP2 cells have significantly increased LVR efflux ratio relative to the parental cells due to the apically directed transport by MDR1 and MRP2 respectively. The efflux ratios in MRP2 and MDR1 transfected cell lines were close to unity in the presence of MK-571 and P-gp 4008 respectively; indicating that LVR efflux by MRP2 and P-gp was completely inhibited by their selective inhibitors. MDCKII-MRP1 cells did not exhibit a significant reduction in the LVR efflux relative to the parental cells, indicating that LVR is not a good substrate for MRP1. Transport studies across MDCKII-Bcrp1 cells indicated that LVR is not transported by Bcrp1 and is not a substrate for this efflux protein. In conclusion, this study presents direct evidence that LVR is effluxed by both P-gp and MRP2 which may contribute to its poor oral bioavailability and limited penetration into the CNS. KeywordsMDCKII-MDR1; MDCKII-MRP2; MDCKII-MRP1; MDCKII-Bcrp1; MDCKII-WT; Pglycoprotein (P-gp); multidrug resistance protein (MRP); breast cancer resistance protein (BCRP); Lopinavir (LVR); uptake; transport; permeability; efflux ratio (ER)

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Active secretion and enterocytic drug metabolism barriers to drug absorption

Cited by 232 publications

References 66 publications

Caco-2 Cell Line

Caco-2 Cell Line

Enhanced oral bioavailability of paclitaxel in mice treated with the P-glycoprotein blocker SDZ PSC 833

Both P-gp and MRP2 mediate transport of Lopinavir, a protease inhibitor

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