Intestinal drug transport and absorption

An Overview ofCaco-2 and Alternatives for Prediction of Intestinal Drug Transport and Absorption... 

More than a decade ago, Caco-2 cells grown on permeable supports were introduced as an experimental tool for mechanistic studies of intestinal drug transport [1-4]. At the same time it was suggested that the Caco-2 model was suitable for screening intestinal drug permeability and predicting the oral absorption potential... 

There are several cell monolayer models that are frequently used for the evaluation of drug permeability and absorption potential (Table 18.1). For a more detailed discussion, please refer to Chap. 8. Caco-2 cells (adenocarcinoma cells derived from colon) are the most extensively characterized and frequently used of the available cell lines [5-9], A unique feature of Caco-2 cells is that they undergo spontaneous enterocyte differentiation in cell culture. Unlike intestinal enterocytes, Caco-2 cells are immortalized and replicate rapidly into confluent monolayers. When the cells reach confluency during culture on a semi-porous membrane, they start to polarize and form tight junctions, creating an ideal system for permeability and transport studies. During the past decade, use of... 

Theoretically, a lipophilic drug may pass through the cell or go around it. If drug has a low molecular weight and is lipophilic, the lipid cell membrane is not a barrier to drug diffusion and absorption. In the intestine, molecules smaller than 500 MW may be absorbed by paracellular drug absorption. Numerous specialized carrier-mediated transport systems are present in the body especially in the intestine for the absorption of ions and nutrients required by the body. 

Artursson, P. and Tavelin, S. (2003) Studies of membrane permeability and oral absorption 6 Caco-2 and emerging alternatives for prediction of intestinal drug transport a general overview, in Drug Bioavailability - Estimation of Solubility, Permeability and Absorption (eds H. van de Waterbeemd, H. Lennernas and P. Artursson), Wiley, pp. 72-89. 

Constantinides, P.P. and Wasan, KM. (2007) Lipid formulation strategies for enhancing intestinal transport and absorption of P-glycoprotein (P-gp) substrate drugs in vitro/in vivo case studies. Journal of Pharmaceutical Sciences, 96 (2), 235-248. 

Chan LM, Lowes S, Hirst BH (2004) The ABCs of drug transport in intestine and liver efflux proteins limiting drug absorption and bioavailability. Eur J Pharm Sci 21 25—51... 

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. 

FIG. 2 Mechanisms of drug transfer in the cellular layers that line different compartments in the body. These mechanisms regulate drug absorption, distribution, and elimination. The figure illustrates these mechanisms in the intestinal wall. (1) Passive transcellular diffusion across the lipid bilayers, (2) paracellular passive diffusion, (3) efflux by P-glycoprotein, (4) metabolism during drug absorption, (5) active transport, and (6) transcytosis [251]. 

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