Intestine efflux systems

Beside membrane transporters such as PepTl and PepT2, which act as absorptive systems, there are transporters like P-gp and the MRP 15, which transport certain drugs actively back into the intestinal lumen. These efflux pumps are located in several tissues including liver, kidney, brain, and intestine [90,91]. In the intestine, efflux systems are predominantly located at the apical side of the epithelial cells. Lipophilic drugs are usually absorbed by the transcellular route so that they are mostly affected by these systems. Interestingly, the intracellular occurring CYP3A metabolizes compounds to substrates that are eliminated by P-gp [92],... 

Hunter, J., Hirst, B. H., Intestinal secretion of drugs the role of P-glycoprotein and related drug efflux systems in limiting oral drug absorption, A dr. Drug Del. Rev. 1997, 25, 129-157. 

Saitoh, H., Aungst, B. J., Possible involvement of multiple P-glyco-protein-mediated efflux systems in the transport of verapamil and other organic cations across rat intestine, Pharm. Res. 1995, 12, 1304-1310. 

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. 

Other cell lines used in permeability studies include the T84 human colonic adenocarcinoma colonic crypt cell model. This line has a reduced carrier expression, secrets mucus, and has very high resistance [31, 32], The IEC cell line is a rat fetal intestinal epithelium cell with higher permeabilities than Caco-2 cells [33], LLC PKi is a pig kidney epithelial cell line with low expression of efflux systems, but expression systems for transport proteins [32], 2/4/A1 cells are a conditionally immortalized rat fetal intestinal epithelium line with crypt cell-like morphology and temperature-sensitive differentiation [34], They form differentiated monolayers with tight junctions, increased brush border enzymes when grown on extracellular matrices with laminin. Transport of drugs with LP in 2/4/A1 monolayers was comparable to that in the human jejunum and up to 300 times faster than that in Caco-2 monolayers. In contrast, the permeability of HP drugs was comparable in both cell lines [34],... 

Efflux systems and presystemic metabolism are, beside other reasons, responsible for low bioavailability of orally administered drugs. Presystemic metabolism itself can be divided into three subtypes luminal metabolism, first-pass intestinal metabolism, and first-pass hepatic... 

As reviewed in this chapter, certain means can be utilized to improve the bioavailability of lipophilic drugs, whether by formulative approach or molecular changes strategies. These means present a number of attractive propositions to the scientist, ranging from an enhancement of drug dissolution and solubilization by lipid-based formulation, increased solubility via the synthesis of a prodrug, specific delivery to the intestinal lymphatics, and reduction in enterocyte-hepatic presystemic metabolism and efflux systems. 

Abstract This chapter attempts to give an overview on the properties of the intestinal epithelium with regard to both, barriers to transcellular (transporter and efflux systems) and paracellular (tight junctional complex) drug absorption and transport systems and tight junction modulation. A short introduction into the relation between the innate immune system and modulation of paracellular permeability is equally given. 

Efflux systems of major importance in the intestinal epithelium are P-glycoprotein (P-gp) (Mizuno et al. 2003), multidrug resistance-associated protein 2 (MRP2) (Jansen et al. 1993), and breast cancer resistance protein (BCRP) (Doyle et al. 1998, Doyle and Ross 2003). The latter is described as a half-transporter and possibly functions as a homodimer (Schinkel and Jonker 2003). Details on the molecular weight, structure, substrates, and expression of P-gp, MRP2, and BCRP are listed in Table 3.2. It needs to be mentioned that expression of these intestinal efflux transporter systems shows high... 

In recent years, it has been found that the barrier function of the intestinal epithelium cannot be adequately described by a combination of metabolic and physical barriers alone. Apically polarized efflux systems are known to be present in cancer cells and represent a major barrier to the uptake of a wide variety of chemotherapeutic agents (i.e. in multi-drag resistance). Efflux systems have also now been identified in normal intestinal and colonic cells, and also at other epithelial sites. 

The advantage of cell culture models is that they are able to measure active transport processes across the cell membranes and not just the interaction of a drug with a lipid bilayer. They can also be used to study passive and active transport routes indeed, much of the knowledge as to the active transport mechanisms in the intestine has been derived from cell culture studies. Despite the predominant route being passive diffusion, the research into transport mechanisms indicates that there are a large number of drugs that are used as substrates for active transporter and efflux systems, and it must therefore be appreciated that multiple transport routes may be involved in the intestinal drug transport. 

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