Biomedical Engineering Reference
In-Depth Information
It is safe to say that transport of drug substances across the intestinal membrane
is a complex and dynamic process. Overall, total drug absorption across a membrane
can be expressed conceptually as the sum of the individual components that occur in
parallel:
J
e
=
J
c
+
J
m
+
J
p
+
J
t
(8)
where
J
e
is the total absorption rate (also referred to as the apparent or effec-
tive flux), and
J
c
,
J
m
,
J
p
, and
J
t
are the transporter-mediated, passive, paracel-
lular, and transcytosis-mediated absorption components, respectively. Transporter-
mediated drug absorption might be a positive or negative value in order to reflect
the direction of transport (e.g., efflux may be designated as a negative value). This
equation becomes more complicated if one attempts to replace
J
c
by the product
of
P
c
(carrier-mediated permeability) and
C
(drug concentration). This is due to
the asymmetrical membrane localization of transporters and consequently different
drug concentrations encountered by them.
11
For example, the drug concentration
available for a brush border membrane-located absorptive transporter (e.g., proton-
dependent peptide transporter PepT1) is the drug concentration in intestinal lumen,
while drug concentration inside enterocytes is supplied for the efflux transporters
at the basolateral membrane (e.g., basolaterally localized peptide transporters). The
quantitative contribution of each component in equation (8) (i.e., the route of transport
across intestinal membrane) to the total absorption rate is influenced by many factors,
including the physicochemical properties of the drugs and physiological conditions
of gastrointestinal (GI) tract. In the following sections we focus on the role of small
intestinal transporters in drug absorption.
16.3. DRUG TRANSPORTERS IN THE SMALL INTESTINE
Numerous drug-transporting membrane proteins (Table 16.1) have been described in
intestinal tissues, and most of them belong to two major transporter superfamilies.
These are the ATP-binding cassette (ABC) and solute carrier (SLC) family.
The well-studied ABC transporters in intestine include ABCB1 [MDR1, P-
glycoprotein (Pgp)], ABCC1, 2, and 3 (MRP1, 2, and 3), as well as ABCG2 [breast
cancer resistance protein (BCRP)]. Available data demonstrate that the expression
levels of ABC transporters vary along the GI tract. MDR1 expression gradually in-
creases from duodenum to colon, and its message RNA level in colon is similar
to that in ileum, which was approximately sixfold higher than in the duodenum.
12
Moreover, characterization of the regional intestinal kinetics of drug efflux in rat
and human intestine revealed that the magnitude of Pgp-mediated efflux correlates
with the expression levels of Pgp. The efflux ratios (B
B
permeability; B and A denote basolateral and apical membrane, respectively) in the
ileum are typically higher than in other regions.
13
The relative abundance of other
ABC transporters message RNA at different sites of intestine was also assessed by
quantitative real-time polymerase chain reaction (PCR).
14
The ranking of transporter
→
A permeability/A
→
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