DRUG TRANSPORT IN THE BRAIN - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 436

protease inhibitors (e.g., saquinavir, ritonavir, nelfinavir, amprenavir) and nonnu-
cleoside reverse transcriptase inhibitors (e.g., efavirenz) may induce significant Pgp
expression in peripheral immune and intestinal cells that have been cultured in these
drug solutions for a period of time. 337 , 348 - 350 In contrast, other researchers have re-
ported that HIV-1 protease inhibitors do not alter Pgp expression and suggest that
drug resistance is associated with mutations in the HIV-1 protease enzyme rather
than an overexpression of Pgp. 351 Similarly, studies have shown that the induction
of drug resistance by selection with increasing concentrations of zidovudine resulted
in cells that were resistant to zidovudine but did not express detectable amounts of
Pgp. 352 It has been proposed that resistance to zidovudine is associated primarily with
mutations in HIV reverse transcriptase and not Pgp overexpression. 352
To date, a few studies have described uptake systems that may be involved in anti-
HIV drug transport in the brain. Our laboratory has reported the functional expression
of a Na + -dependent thymidine transporter 248 as well as an organic cation transporter-
like uptake system for zidovudine in cultured rat microglia. 353 Furthermore, nucleo-
side transporters such as hCNT1 have been implicated in the low-affinity uptake of
zidovudine and stavudine. 354
14.4.3. Epilepsy
Epilepsy is characterized by recurrent seizures and is one of the most common neuro-
logical disorders worldwide. 355 Approximately one-third of epileptic patients remain
pharmacoresistant despite significant advances in antiepileptic drug therapy. 356 The
consequences of uncontrolled epilepsy are severe and include decreased life span,
bodily injury, neuropsychological impairment, and social disability. 357 Resistant pa-
tients often do not respond to drug therapy with several, if not all, antiepileptics, even
though these compounds may act by different pharmacological mechanisms. 358 Inter-
estingly, the blood concentrations of antiepileptic drugs in resistant patients usually
fall within the normal therapeutic range, suggesting an intrinsic mechanism in the
brain that limits the accumulation of antiepileptic drugs.
Tishler and colleagues were the first group to describe the role of drug transporters
in the development of pharmacoresistant epilepsy. 359 They reported overexpression
of Pgp in brain tissue isolated from pharmacoresistant patients, which implies that
the development of MDR may also be relevant to the treatment of epilepsy. Pgp ex-
pression has also been reported in the capillary endothelium in brain tissue of patients
with intractable epilepsy. 360 In fact, the brain expression of Pgp may be up-regulated
in drug-resistant epilepsy. For example, Rizzi et al. induced seizures in rats by kainate
injection and observed increased Pgp expression in the limbic system after repeated
seizure activity. 361 Interestingly, exposure to antiepileptic drugs did not increase Pgp
expression in rats, suggesting that Pgp upregulation is mediated by factors related to
seizure activity itself. 361 MRP1 expression has also been detected in several brain mal-
formations characteristic of refractory epilepsy, including dysplastic neurons, reactive
astrocytes, and the glial element of focal cortical dysplasia (i.e., balloon cells). 362 , 363
In addition, up-regulation of MRP2 and MRP5 mRNA transcripts and protein has been
reported in medically intractable epilepsy. 360 , 364 Interestingly, the protein expression