DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

96
SECTION I
GENERAL PRINCIPLES
Noncompetitive inhibition assumes that the
inhibitor has an allosteric effect on the transporter, does
not inhibit the formation of an intermediate complex of
substrate and transporter, but does inhibit the subsequent
translocation process.
V I K C
i
v =
/( 1 + / ) ⋅
max
(Equation 5–11)
K + C
m
Uncompetitive inhibition assumes that inhibitors
can form a complex only with an intermediate complex
of the substrate and transporter and inhibit subsequent
translocation.
V I K C
i
v =
/ ( 1+
/
max )⋅
(Equation 5–12)
K / 1+
I / K C
VECTORIAL TRANSPORT
m
( ) +
Asymmetrical transport across a monolayer of
polarized cells, such as the epithelial and endothelial
cells of brain capillaries, is called vectorial transport
(Figure 5–5). Vectorial transport is important in the efficient
transfer of solutes across epithelial or endothelial
barriers. For example, vectorial transport is important
for the absorption of nutrients and bile acids in the
intestine. From the viewpoint of drug absorption and
disposition, vectorial transport plays a major role in
hepatobiliary and urinary excretion of drugs from the
blood to the lumen and in the intestinal absorption of
drugs. In addition, efflux of drugs from the brain via
i
brain endothelial cells and brain choroid plexus epithelial
cells involves vectorial transport. The ABC transporters
mediate only unidirectional efflux, whereas
SLC transporters mediate either drug uptake or efflux.
For lipophilic compounds that have sufficient
membrane permeability, ABC transporters alone are
able to achieve vectorial transport without the help of
influx transporters (Horio et al., 1990). For relatively
hydrophilic organic anions and cations, coordinated
uptake and efflux transporters in the polarized plasma
membranes are necessary to achieve the vectorial
movement of solutes across an epithelium. Common
substrates of coordinated transporters are transferred
efficiently across the epithelial barrier (Cui et al., 2001;
Sasaki et al., 2002).
In the liver, a number of transporters with different substrate
specificities are localized on the sinusoidal membrane (facing
blood). These transporters are involved in the uptake of bile acids,
amphipathic organic anions, and hydrophilic organic cations into the
hepatocytes. Similarly, ABC transporters on the canalicular membrane
(facing bile) export such compounds into the bile. Multiple
combinations of uptake (OATP1B1, OATP1B3, OATP2B1) and
efflux transporters (MDR1, MRP2, and BCRP) are involved in the
efficient transcellular transport of a wide variety of compounds in
the liver by using a model cell system called “doubly transfected
cells,” which express both uptake and efflux transporter on each side
(Ishiguro et al., 2008; Kopplow et al., 2005; Matsushima et al.,
2005). In many cases, overlapping substrate specificities between
the uptake transporters (OATP family) and efflux transporters (MRP
family) make the vectorial transport of organic anions highly efficient.
Similar transport systems also are present in the intestine, renal
tubules, and endothelial cells of the brain capillaries (Figure 5–5).
Small intestine:
absorption
Liver:
hepatobiliary
transport
Kidney:
tubular secretion
Brain capillaries:
barrier function
SLC
SLC
ABC
ABC
ATP ATP ATP
ABC SLC SLC
ABC
ATP
ATP
ABC
SLC
ATP
ABC
SLC
SLC
Blood
Figure 5–5. Transepithelial or transendothelial flux. Transepithelial or transendothelial flux of drugs requires distinct transporters at
the two surfaces of the epithelial or endothelial barriers. These are depicted diagrammatically for transport across the small intestine
(absorption), the kidney and liver (elimination), and the brain capillaries that comprise the blood-brain barrier.