MULTIDRUG RESISTANCE PROTEIN: P-GLYCOPROTEIN - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 244

that a drug will fail to be effective in animal and human trials if it is a Pgp substrate,
many pharmaceutical companies have added interactions with Pgp to their drug dis-
covery screening processes in an attempt at early identification of these compounds.
This is especially important for drugs targeted to the central nervous system.
Blockade of Pgp with modulators can have dramatic effects on systemic drug dis-
position by decreasing drug elimination through the intestine, bile, and urine. Initially,
the focus was on using modulators with anticancer drugs to improve the efficacy of
chemotherapy treatment, 190 but later it was realized that modulators could be useful
in altering the pharmacological behavior of many drugs, to improve their delivery.
Modulators may enhance intestinal drug absorption and increase drug penetration
through biologically important protective barriers such as the blood-brain, blood-
cerebrospinal fluid, and maternal-fetal barriers. Delivery of drugs to the brain, either
to treat epilepsy and other central nervous system diseases, AIDS, or brain tumors
such as gliomas might therefore be increased by addition of an effective modulator.
This has been shown to be feasible in a mouse model using highly effective modula-
tors such as PSC833 and GF120918. 191-193 The future development of more effective
Pgp modulators may make enhanced drug delivery to the brain a realistic clinical goal.
First-generation modulators (e.g., verapamil, quinidine) were poor Pgp inhibitors,
requiring high plasma levels to reverse MDR, which could not be obtained without
unacceptable patient toxicity. In addition, these drugs were used clinically to treat other
medical conditions and produced pharmacological side effects. Several advanced
MDR-reversing agents are in various stages of development. 194 Second- and third-
generation MDR inhibitors with good clinical potential include PSC833, GF120918,
XR9576, LY335979, VX-710, and OC 144-093.
Several Pgp modulators also inhibit one or more cytochrome P450 enzymes (e.g.,
CYP3A4) that function to metabolize drugs. Thus, it has been widely observed that
treatment with Pgp modulators decreases drug clearance, resulting in increased toxi-
city of coadministered drugs. Plasma drug levels remain higher for longer, increasing
the “area under the curve” (AUC) and often necessitating a substantial reduction in
drug dose to avoid toxicity. More selective third-generation Pgp modulators, such
as LY335979 and XR9576, do not inhibit the CYP enzymes and show only small
increases in AUC, so that dose reduction is not needed. Understanding how Pgp mod-
ulators affect the toxicity and pharmacokinetics of other drugs is important for the
design of clinical trials of MDR modulation.
10.15. MODULATION OF P-GLYCOPROTEIN IN CANCER TREATMENT
A major reason for the failure of chemotherapy treatment to cure human cancers is the
ability of tumor cells to become resistant to several anticancer drugs simultaneously.
Many mechanisms are known to contribute to MDR in tumor cells, of which the
presence of multidrug efflux pumps is only one. Three ABC family members, Pgp,
MRP1 (ABCC1), and BCRP (ABCG2), are likely to be the major drug efflux pumps
expressed in human cancers. 195 Tumor cells are notoriously heterogeneous, and corre-
lations between drug resistance and the expression of efflux pumps have been difficult