Biomedical Engineering Reference
In-Depth Information
toxic xenobiotics, the secretion of metabolites and xenobiotics into bile, urine, and the
lumen of the gastrointestinal tract, and possibly the transport of hormones from the
adrenal gland and the uterine epithelium. These ideas have been strongly supported
by studies on transgenic knockout mice lacking one or both of the genes encoding
the drug-transporting Pgps Abcb1a and Abcb1b. Both single- and double-knockout
mice are fertile, viable, and phenotypically indistinguishable from wild-type mice
under normal conditions. So Pgp does not appear to fulfill any essential physiological
functions. However, Pgp knockout mice showed radical changes in the way that they
handled a challenge with many drugs.
14
mdr3 knockout mice displayed a disrupted
blood-brain barrier and were 100-fold more sensitive to the pesticide ivermectin,
which was neurotoxic to the animals.
15
This Pgp isoform appears to play the major
role in preventing accumulation of drugs in the brain.
15
,
16
The double-knockout
mouse has proved useful in evaluating the effect of Pgp-mediated transport on drugs
that are targeted to the central nervous system.
17
Certain dogs of the collie lineage
18
and several other dog breeds
19
,
20
have a naturally occurring lack of Pgp due to a
frameshift mutation in the MDR1 gene and are also hypersensitive to ivermectin. To
date, no human null alleles have been reported, despite widespread use of drugs that
are Pgp substrates.
Pgp in the intestinal epithelium plays an important role in the extrusion of many
drugs from the blood into the intestinal lumen, and in preventing drugs in the intestinal
lumen from entering the bloodstream. Pgp activity can therefore reduce the absorption
and oral bioavailability of those drugs that are transport substrates.
One important goal in clinical medicine has been the development of techniques
for in vivo functional imaging of Pgp-mediated drug transport in normal tissues
and tumors and its inhibition by specific Pgp modulators. The radiopharmaceuti-
cal technetium-99m-sestamibi (
99m
Tc-MIBI) has been validated as a Pgp transport
substrate. Scintigraphic studies of human subjects showed rapid clearance of the ra-
diotracer from normal liver and kidneys in vivo; however, it was retained selectively in
these organs after administration of the Pgp modulator, PSC833.
21
Later studies have
shown the prognostic value of this approach in different types of tumors, including
breast and lung cancer, sarcoma, and lymphoma.
22
The activity of Pgp at the human
blood brain barrier has also been imaged using positron emission tomography using
11
C-labeled verapamil or carvedilol (Pgp transport substrates).
23
10.4. P-GLYCOPROTEIN SUBSTRATES AND MODULATORS
Pgp has the ability to interact with literally hundreds of structurally diverse
substrates
(see Table 10.1), which are generally nonpolar, weakly amphipathic compounds,
and include natural products, anticancer drugs, steroids, fluorescent dyes, linear and
cyclic peptides, and ionophores. The unusual promiscuity of the transporter has made
it difficult to find “nonsubstrates.” Potential physiological substrates for Pgp could
include peptides, steroid hormones, lipids, and small cytokines, such as interleukin-
2, intereukin-4, and interferon-
. However, there is little information on the extent
to which endogenous compounds are transported by Pgp in vivo. Identification of
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