Biomedical Engineering Reference
In-Depth Information
lipophilicity, polarity and molecular size) to cross both the apical and basolateral
membrane as well as the lipophilic barriers of cells (Hunter and Hirst
1997
). The
transcellular transport can be performed across enterocytes or, in a lesser extent,
M-cells. M-cells are specialized phagocytic enterocytes found in the follicle-
associated epithelium of the Peyer's patches (Clark et al.
2001
). They are specialised
in the capture and transport of bacteria, virus, macromolecules and particles from
the gut lumen to immune cells across the epithelial barrier, and thus are important
in stimulating mucosal immunity. Unlike their neighbouring cells (enterocytes),
they have the unique ability to take up compounds from the lumen of the small
intestine via endocytosis or phagocytosis and, then, deliver them via transcytosis to
dendritic cells (DCs) and lymphocytes located in an unique pocket-like structure on
their basolateral side. M-cells, which possess broader microfolds, differ from
normal enterocytes in that they lack microvilli on their apical surface and that they
are far less abundant (Clark et al.
2001
; Corr et al.
2008
).
The paracellular transport or the transference between adjacent cells (Fig.
1a
-4)
appear to be restricted to small hydrophilic molecules (approximately <350 Da)
(Gaucher et al.
2010
). This extracellular route across the epithelium is based on the
establishment of an electrochemical gradient derived from differences in concentra-
tion, electrical potential and/or hydrostatic pressure between the two sides of the
epithelium. Nevertheless, the total contribution of the paracellular pathway to general
drug transport is, in general, very discrete (Artursson et al.
2001
; Palm et al.
1996
).
Drugs that are structural analogues of natural compounds can gain entry into the
cell by carrier
-
mediated mechanisms (Fig.
1a
-6). These influx transporters can
increase the drug absorption by specific binding of the compound with the specific
carrier, which is located on the surface of the cellular lipid bilayer (Blanchette et al.
2004
). Compounds that are substrates of these transporters exhibit higher intestinal
absorption than expected for a mechanism of transport by diffusion. There are more
than 400 membrane transporters, belonging to two major superfamilies: the ATP
binding cassette (ABC) and the solute carrier (SLC) families (Sugano et al.
2010
).
However, their substrate specificity is not absolute, and carrier-mediated transport
is only available to a certain number of drugs.
On the other hand, drug efflux pumps like P-glycoprotein (P-gp) (Fig.
1a
-2) play
a major role in the absorption of many drugs. P-glycoprotein is best known for its
ability to transport drug substrates out of cells in a variety of tissues, including the
intestine (Sparreboom et al.
1997
). The intestinal P-glycoprotein is the 170-kDa
product of the human MDR1 gene and member of the ABC family of transport pro-
teins (Sparreboom et al.
1997
). Both the expression and the function of P-glycoprotein
have been related to considerable variability in oral drug absorption (Hunter and
Hirst
1997
; Hunter et al.
1993
). It is present in the columnar epithelial cells
(enterocytes) of the lower gastrointestinal tract (Varma et al.
2006
). Given its apical
distribution on the enterocyte, P-gp is exquisitely positioned to limit the absorption
of substances that the cell perceives as harmful. Unlike some conventional trans-
porter, P-gp does not transport a specific substrate but a wide variety of chemically
most diverse compounds (Neudeck et al.
2004
). Among others, many important
anticancer drugs currently in use are substrates of the P-gp such as doxorubicin,
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