DRUG TRANSPORT IN THE BRAIN - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 435

Several studies have demonstrated that many neurotoxic mediators released during
brain HIV-1 infection, particularly cytokines, can alter drug transporter expression.
Studies using isolated rat hepatocytes 330 and isolated rat brain capillaries 331 have

shown that cytokines (e.g., TNF , IL-6) can alter Pgp molecular expres-

sion and functional activity. Using a human hepatoma cell line (HepG2), Lee and
Piquette-Miller (2003) demonstrated that treatment with IL-1

, IL-1

and IL-6 can signif-
icantly increase both MRP1 gene expression and functional activity. 332 Therefore,
it is not unexpected that cytokine secretion during HIV-1 infection can lead to al-
tered drug transporter expression and changes in antiretroviral drug permeation and
distribution in the CNS. In fact, our laboratory has recently shown increased cy-
tokine secretion in the presence of the HIV-1 viral envelope glycoprotein gp120 and
that these cytokines are involved in the regulation of Pgp expression in cultured
rat astrocytes. 333
In addition to the secretion of inflammatory cytokines, other studies have shown
that the HIV-1 virus and its related proteins can also alter the functional expression
of drug transporters. An early study reported that Pgp expression was up-regulated
upon HIV-1 infection of both a T-cell and monocytic cell line. 334 Andreana and col-
leagues also reported increased Pgp expression in peripheral blood mononuclear cells
(PBMCs) isolated from HIV-infected patients. 335 These observations are somewhat
controversial, as other studies have shown that various subsets of PBMCs may ac-
tually express lower levels of Pgp in HIV-1-infected patients compared to healthy
volunteers. 336 , 337 The fact that soluble viral proteins (e.g., gp120, Tat) are secreted
during active HIV-1 infection has generated significant interest. Recently, Tat has
been shown to increase in vitro both Pgp and MRP1 expression at the BBB. 338 , 339
Studies in our laboratory have shown that Pgp expression and functional activity are
decreased significantly in cultured astrocytes treated with gp120. 333
Although implementation of HAART has been successful in reducing systemic
viral load in HIV-1-seropositive patients, HIVE remains refractory to drug therapy,
possibly due to the poor permeation of antiretroviral drugs into the brain. For exam-
ple, antiretroviral drugs, particularly HIV-1 protease inhibitors, penetrate the CNS
poorly. 340 One possible mechanism for the low brain concentrations of antiretrovi-
ral drugs is the expression of ABC transporters (e.g., Pgp, MRPs, ABCG2) at the
brain barriers and in brain cellular targets of HIV-1 infection (e.g., microglia, as-
trocytes). HIV-1 protease inhibitors are well-known transport substrates for both
Pgp and MRPs. 50 , 76 , 341 , 342 In addition, nucleotide reverse transcriptase inhibitors
(e.g., PMEA) have been shown to interact with Mrp4 and Mrp5 in cultured rat
microglia. 82 Zidovudine monophosphate and abacavir have also been shown to be
MRP4 substrates, 79 , 343 whereas stavudine is an MRP5 substrate. 343 Additionally,
MRP8 has been shown to be involved in the cellular efflux of PMEA and zalcitabine
but not zidovudine or lamivudine. 344 Antiretroviral agents that have been shown
to be substrates for ABCG2 include the nucleoside reverse transcriptase inhibitors
zidovudine and stavudine. 345 , 346 In contrast, HIV-1 protease inhibitors (e.g., riton-
avir, saquinavir, nelfinavir) have been shown to be inhibitors but not substrates of
ABCG2. 347 Other studies suggest that antiretroviral drugs may be responsible for
increased Pgp levels in HIV-infected cells. Several groups have reported that HIV-1