MULTIDRUG RESISTANCE PROTEIN: P-GLYCOPROTEIN - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 226

TABLE 10.1. Pgp Substrates and Modulators
Substrates

Modulators

Ca 2 + channel blockers
verapamil
nifedipine
azidopine
dexniguldipine
Calmodulin antagonists
trifluoperazine
chloropromazine
trans -flupenthixol
Cyclic peptides
cyclosporin A
PSC833
Steroids
progesterone
tamoxifen
cortisol
Miscellaneous
GF120918
LY335979
XR9576
OC144-093
disulfiram
quinidine
chloroquine
reserpine
amiodarone
terfenadine

Vinca alkaloids
vinblastine
vincristine
Anthracyclines
doxorubicin
daunorubicin
Taxanes
paclitaxel
docetaxel
Epipodophyllotoxins
etoposide
teniposide
Steroids
aldosterone
dexamethasone
HIV protease inhibitors
indinavir
saquinavir
nelfinavir
ritonavir
Analgesics
morphine
Cardiac glycosides
digoxin
Antihelminthics
ivermectin

Detergents
Triton X-100
nonylphenol ethoxylate
Fluorescent dyes
rhodamine 123
tetramethylrosamine
Hoechst 33342
LDS-751
calcein acetoxymethyl ester
Linear/cyclic peptides
ALLN
NAc-LLY-amide
leupeptin
pepstatin A
Ionophores
gramicidin D
nonactin
beauvericin
Cytotoxic agents
colchicine
actinomycin D
mitoxantrone
Miscellaneous
loperamide
cimetidine

a specific compound as a Pgp substrate is often indirect, although more specific
spectroscopic approaches now allow measurement of binding affinity. 24 Direct mea-
surement of Pgp-mediated transport has been carried out for only a small fraction
of these substrates. Work with reconstituted Pgp has shown that it is an active trans-
porter, generating a substrate concentration gradient across the membrane. 25 , 26 In
intact cells, the drug concentration in the cytosol is kept low enough to circumvent
cytotoxicity, and they thus become multidrug resistant.
A second class of compounds exists which interact with Pgp, the modulators (also
known as MDR chemosensitizers, reversers, or inhibitors; see Table 10.1). Modulators
are able to reverse MDR in intact cells in vitro, by interfering with the ability of Pgp
to efflux drug and thus generate a drug concentration gradient. The ability to block
the action of Pgp selectively is of importance clinically, whether the goal is to achieve
more efficacious cancer chemotherapy, improve drug bioavailability and uptake in the
intestine, or deliver drugs to the brain. Numerous pharmacologic agents have been
identified as Pgp modulators, many by serendipity or trial and error (see Table 10.1).