DRUG TRANSPORT IN THE BRAIN - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 416

Mrp5

MRP8

MRP4

Mrp3 MRP6

Neurons

rPGT

OCT2

Oat1

Astrocytes

Microglia

OCTN2

FIGURE 14.2. Xenobiotic transport mechanisms in the brain parenchyma. The proposed
expression of ABC superfamily transporters, organic anion and cation transporters, nucleo-
side transporters, and peptide transporters is depicted in astrocytes, microglia, and neurons.
Although expression of these transporters has been shown, localization and function remain
to be demonstrated. The localization of membrane drug transporters in oligodendrocytes has
not been well characterized and therefore is not included in this figure. The arrows indicate
the direction of substrate transport. References are indicated in the text. ( See insert for color
representation of figure. )

transporters such as Pgp, MRP isoforms, and BCRP are also important determinants
of drug uptake, distribution, and excretion. These transporters have all been impli-
cated in the development of the multidrug resistance (MDR) phenotype. The MDR
phenotype is defined as the simultaneous resistance to several structurally unrelated
compounds. MDR does not result from independent genetic mutations which confer
resistance to a single xenobiotic. 40

P-Glycoprotein The ABC superfamily of proteins contains many membrane-bound
energy-dependent transporters involved in the cellular efflux of endogeneous and ex-
ogeneous compounds. P-glycoprotein (Pgp), a well-characterized ABC transporter
discovered in Toronto by Victor Ling, 41 , 42 is a 170-kDa integral membrane protein
encoded by the MDR gene. 40 Two isoforms of the MDR gene, designated MDR1 and
MDR2, have been cloned and sequenced in humans. 43 , 44 In rodents, Pgp is encoded
by the mdr1a, mdr1b, and mdr2 genes. While MDR2/mdr2 is expressed primarily
in the liver and has been implicated in the translocation of phosphatidylcholine into