Absorptive intestinal transporter

Structural Requirements for Targeting Absorptive Intestinal Transporters 245... 

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. 

M Asgharnejad. Investigation into intestinal transport and absorption of an amino acid, amino acid analougue and its peptideomimetic prodrug. PhD dissertation, Chapter IV. pp 109-127, The University of Michigan, 1992. 

Fig. 7.1. The intestinal permeability of drugs in vivo is the total transport parameter that may be affected by several parallel transport mechanisms in both absorptive and secretory directions. Some of the most important transport proteins that may be involved in the intestinal transport of drugs and their metabolites across intestinal epithelial membrane barriers in humans are displayed.

The transporter-mediated uptake of drugs into epithelial cells is emerging as a new trend in biopharmaceutics [6]. Utilization of the intestinal epithelial transporters to facilitate the absorption of drugs or prodrugs appears to be an attractive delivery approach. The purpose of this chapter is to describe the pharmaceutical and medicinal relevances of intestinal transporters. This will provide new knowledge for strategies to enhance intestinal absorption of drugs. 

Polarized tissues directly involved in drug absorption (intestine) or excretion (liver and kidney) and restricted drug disposition (blood-tissue barriers) asymmetrically express a variety of different drug transporters in the apical or basolateral membrane resulting in vectorial dmg transport. This vectorial dmg transport is characterized by two transport processes the uptake into the cell and subsequently the directed elimination out of the cell (Figure 15.3). Because the uptake of substances... 

Ruiz-Balaguer N, Nacher A, Casabo VG and Sanjuan MM (2002) Intestinal Transport of Cefuroxime Axetil in Rats Absorption and Hydrolysis Processes. Int J Pharm 234 pp 101-111. 

In addition to screening molecules for intestinal absorption, Caco-2 cells have also been used to study mechanisms of drug transport. For many compounds, intestinal permeation involves a transporter to either aid or limit transepithelial transport. The value of Caco-2 cells in this type of studies is due to the fact that these cells express various membrane transporters relevant to drug absorption.1719-23,28,30 However, when interpreting results of studies that involve carrier-mediated transport, discretion, and scaling factors may be required because of the difference in expression level of transporters between in vitro and in vivo systems.12 Another important consideration in carrier-mediated transport studies is that some transport systems in Caco-2 cells may achieve maximal expression level at different days in culture.17,21,38,74 Thus, validation of Caco-2 cells for mechanistic studies should include the identification of the time for optimal expression of transporters as well as the qualitative evaluation of the transporters to establish that they are representative of the native intestinal transporters. 

Powell, D.W., Barrier function of epithelia. Am. J. Physiol., 241 G275-G288 (1981). Nellans, H.N., Paracellular intestinal transport modulation of absorption, Adv. Drug Del. Rev., 7 339-364 (1991). 

Active transporters are thought to play an important role in the pharmacokinetics of drugs, not only because they can regulate the permeability of drugs as substrate-specific efflux or influx pumps, but also because of their widespread presence across in vivo membrane systems, from the intestinal epithelia to the BBB. Generally speaking, the absorption direction transporters tend to have narrower substrate specificity than the excretion direction transporters. Active transporters also play a significant role in biliary and renal excretion. 

Nellans, H.N. 1991. Mechanism of peptide and protein absorption, paracellular intestinal transport Modification of absorption. Adv Drug Deliv Rev 7 339. 

Mizuma, T., A. Koyanagi, and S. Awazu. 1997. Intestinal transport and metabolism of analgesic dipeptide, kyotorphin Rate-limiting factor in intestinal absorption of peptide as drug. Biochim... 

The cholesterol-lowering properties of dietary plant sterols have been known for decades (Best et al., 1954 Peterson, 1951 Poliak, 1953), due specifically to reductions in cholesterol absorption. Inverse correlations between plant sterol intake and cholesterol absorption have been reported in animals (Carr et al., 2002 Ntanios and Jones, 1999) and humans (Ellegard et al., 2000). The exact mechanism by which plant sterols inhibit cholesterol absorption is unclear, and several mechanisms of action have been proposed, including (1) competition with cholesterol for solubilization in micelles within the intestinal lumen, (2) cocrystallization with cholesterol to form insoluble crystals, (3) interaction with digestive enzymes, and (4) regulation of intestinal transporters of cholesterol. 

Homan, R. and Hamelehle, K.L. 1998. Phospholipase A2 relieves phosphatidylcholine inhibition of micellar cholesterol absorption and transport by human intestinal cell line Caco-2. J. Lipid Res. 39, 1197-1209. 

Hui, D.Y. and Howies, P.N. 2005. Molecular mechanisms of cholesterol absorption and transport in the intestine. Semin. Cell Dev. Biol. 16, 183-192. 

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