DRUG TRANSPORT IN THE BRAIN - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 438

of Parkinson's disease has led to a significant interest in transporters that may be
involved in the uptake and distribution of these toxins in the brain. For example, it has
been suggested that genetic polymorphisms in the MDR1 gene may represent a risk
factor for Parkinson's disease since Pgp is involved in the active efflux of toxins from
the brain. In fact, studies using mdr1a(

) mice have shown that Pgp is prominently
involved in limiting the accumulation of toxic pesticides in the CNS. 374 Nonetheless,
no published research has directly examined the role of drug transporters in either the
pathogenesis and/or brain distribution of anti-Parkinsonian drugs.

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14.5. CONCLUSIONS

The dynamic and highly controlled environment of the brain is regulated, in part,
by the blood-brain and blood-CSF barriers. Within this intricate environment exists
the cellular components of the brain parenchyma (i.e., astrocytes, microglia, oligo-
dendrocytes, and neurons). Each brain cellular compartment possesses a specific and
selective set of metabolic enzymes, receptor proteins, and secretory factors that serve
to maintain the homeostatic environment required for normal brain physiology. In ad-
dition, the localization and expression of putative drug transporters in these barriers
play a critical role in the influx and efflux of numerous endogeneous and exogeneous
substrates, which ultimately exert a significant impact in the overall pharmacokinetic
and pharmacodynamic profile of drugs in the brain. The localization and functional
expression of influx transporters (e.g., OATs, OCTs, OATPs, NTs, PTs) as well as
the efflux transporters (e.g., Pgp, MRPs, ABCG2) at the brain barriers and within
the brain parenchyma suggest that complex drug-transporter interactions may occur
during the pharmacotherapy of CNS disease. Further investigation is required to char-
acterize drug transporters at the parenchymal barrier sites so as to fully understand
their clinical role.

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