Intestinal epithelial cells, drug transporters

Both influx and efflux transporters are located in intestinal epithelial cells and can either increase or decrease oral absorption. Influx transporters such as human peptide transporter 1 (hPEPTl), apical sodium bile acid transporter (ASBT), and nucleoside transporters actively transport drugs that mimic their native substrates across the epithelial cell, whereas efflux transporters such as P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP), and breast cancer resistance protein (BCRP) actively pump absorbed drugs back into the intestinal lumen. 

Wils, P. Wamery, A. Phung-Ba, V. Legrain, S. Scherman, D., High lipophilicity decreases drug transport across intestinal epithelial cells, J. Pharmacol. Exp. Ther. 269, 654-658 (1994). 

Some laboratories have found an alternative to the short-term cultures by using cell lines other than Caco-2 cells. The most popular of these is Madin-Darby canine kidney (MDCK) cells, an epithelial cell line from the dog kidney. MDCK cells have been suggested to perform as well as Caco-2 cells in studies of passive drug permeability [56]. These cells have also been used to optimise the conditions for studies of low-solubility drugs [53]. However, as noted previously, the active transport processes of this cell line can be quite different to those of Caco-2 cells [28-30], Another cell line that only requires short-term culture is 2/4/A1, which is a conditionally immortalised rat intestinal epithelial cell line [86]. The 2/4/A1 cell line is discussed in Section 4.3.2.2 below. 

K. Hosoya, M. Tomi, M. Takayama, Y. Komokata, D. Nakai, T. Tokui, K. Nishimura, M. Ueda, M. Obinata, S. Hori, S. Ohtsuki, G. L. Amidon, and T. Terasaki. Transporter mRNA expression in a conditionally immortalized rat small intestine epithelial cell line (TR-SIE). Drug Metabol. Pharmacokinet. 19 264-269 (2004). 

Many drugs have been recognized to cross the intestinal epithelial cells via passive diffusion, thus their lipophilicity has been considered important. However, as described above, recent studies have demonstrated that a number of drug transporters including uptake and efflux systems determine the membrane transport process. In this chapter, we provide an overview of the basic characteristics of major drug transporters responsible not only for absorption but also for disposition and excretion in order to delineate the impact of drug transport proteins on pharmacokinetics. 

Figure 23.3 Drug transporters in the intestinal epithelial cells. PEPT1 is the most characterized transporter for intestinal drug absorption. The basolateral peptide transporter, which is not identified at the molecular level, also plays important roles. OATP-B, OCTN2 and MRP3 may be responsible for the intestinal absorption of some drugs. On the contrary, ABC transporters such as P-gp located at brush-border membranes mediated the efflux of drugs from intestinal epithelial cells, contributing to the low bioavailabihty of drugs such as the immunosuppressive agent, tacrolimus.

Kotze, A.F., Thanou, M.M., LueBen, H.L., De Boer, A.G., Verhoef, J.C., and Junginger, H.E., Enhancement of paracellular drug transport with highly quaternized N-trimethylchitosan chloride in neutral environments In vitro evaluation in intestinal epithelial cells (Caco-2), J. Pharm. Sci., 88 253-257 (1999). 

Human PepTl was initially cloned from intestine (92) and was found to be localized to the brush border of intestinal epithelial cells (93) and in SI segment of apical proximal tubules (94). PepTl transports (3-lactam antibiotics (95), antiviral drugs such as valacyclovir and valganciclovir (96), and the angiotensin converting enzyme inhibitor captopril (97). Polymorphisms have been reported, however little is known regarding their functional consequences (64). 

Caco-2 cells, especially the human intestinal epithelial cell line, have been proposed and used for the simulation and prediction of intestinal drug absorption after oral administration. These membranes of cells have useful properties for correlation with in vivo data such as enzymatic and transporter systems [24]. 

Chao AC, Taylor MT, Daddona PE, Broughall M, Fix JA (1998b) Molecular weight-dependent paracellular transport of fluorescent model compounds induced by palmitoyl-carnitine chloride across the human intestinal epithelial cell line Caco-2. J Drug Targeting 6 37 13... 

Enhancement of paracellular drug transport with highly quaternized V-trimethyl chitosan chloride in neutral environment in vitro evaluation in intestinal epithelial cells (Caco-2). J. Pharm. Sci. 88 253-257. 

Jumarie Cand Malo C (1991) CACO-2 cells cultured in serum-free medium as a model for the study of enterocytic differentiation in vitro. J Cell Physiol 149 24-33 Karlsson J, Ungell AL, Artursson P (1994) Effect of an oral rehydration solution on paracellular drug transport in intestinal epithelial cells and tissues assessment of charge and tissue selectivity. Pharm Res 11 248... 

St John s wort can cause drug interactions by inducing hepatic microsomal drug-metabolizing enzymes or the drug transporter P-glycoprotein, which causes a net efflux of substrates, such as amitriptyline, from intestinal epithelial cells into the gut lumen (SEDA-24,12). In 12 patients (9 women, 3 men) the addition of St John s wort 900 mg/ day to amitriptyline 150 mg/day led to a 20% reduction in plasma amitriptyline concentrations, while nortriptyline concentrations were almost halved (210). 

Carrier-Mediated Intestinal Transport. Various carrier mediated systems (transporters) are present at the intestinal brush border and basolateral membrane for theabsorption of specific ions and nutrients essential for the body. Many drugs are absorbed by these carriers because of the structural similarity to natural substrates. An intestinal transmembrane protein, P-Glycoprotein (F-Gp) appears to reduce apparent intestinal epithelial cell permeability from lumen to... 

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