Carrier Mediated Transport

Intestinal epithelial cell membranes are highly polarized. Apical membrane faces the external lumen with many microvilli to increase the membrane surface area. Many membrane transporters are located in this side facilitating absorption for most nutrients and many drugs, while basolateral membrane is toward blood (Rouge et al., 1996; Shin et al., 2003; Anderle et al., 2004) (Fig. 4.3).

Depending on the direction and category of transported solutes, drug carrier to mediate transport can also be classified into uniporter, symporter, and antiporter. Uniporter is the carrier-mediated transport with single solute; symporter facilitates the transport of two solutes with same direction, while antiporter facilitates the transport of two solutes with opposite directions. Based on the concentration gradient of the solutes and energy involved in the process, drug carrier can be classified into facilitated diffusion and active transport.

4.2.2.1 Facilitated Diffusion

Carrier proteins are involved in facilitated diffusion. This process does not need energy. Similar to passive diffusion, transport direction of facilitated diffusion depends on the solutes concentration gradient (from higher concentration to lower

Intestinal lumen Apical membrane

Basal membrane rBAT b0+AT

TAUT

ATB0

hPepT1

MCT1

MOAT MDR FATP4 IBAT

SGLT1 GLUT5

GLUT2

Figure 4.3. Apical and basolateral transporters coupling for absorption (See Color Plate II)

OCT3

GLUT2

Figure 4.3. Apical and basolateral transporters coupling for absorption (See Color Plate II)

concentration) (Cainelli et al., 1974; Feher, 1983). However, facilitated diffusion has higher transport rate than what would be expected from passive diffusion alone.

4.2.2.2 Active Transport

Active transport is the primary mode by which molecules are transported against electrical and/or chemical concentration gradients. The process involves a membrane bound protein molecule that binds reversibly to the solute molecule at a specific site. The complex then undergoes a change in conformation that translocates the solute to the other side of the membrane. Factors that can affect this transport include energy, temperature, and stereospecificity of the molecule. Similar to enzyme kinetics, active transport also exhibits saturable kinetics and can be inhibited by similar structural analogs.

where J is the drug flux (mg s-1); Jmax, the maximum drug flux; C, the drug concentration (mg ml-1); and Km, the drug affinity to carrier (mg ml-1). At low concentration, C ^ Km, first order absorption prevails

At high concentration, C ^ Km, zero-order absorption prevails

In contrast to passive diffusion, drugs with active transport absorption mechanism may have a concentration dependent and/or dose-dependent absorption (Fig. 4.4). Drug flux can be competitively inhibited by other substrates.

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