the liver (Shitara and Sugiyama, 2003). Metformin, a biguanide antidiabetic
drug, is distributed into the liver via Oct1 and into the kidney via Oct2 (Shitara
and Sugiyama, 2006).
One of the important tissue barriers for xenobiotics is blood–brain barriers
(BBB). Currently, several ABC transporters, P-gp, BCRP, MRP1, and SLC
transporters, amino acid, glucose, organic cation, and organic anion
transporters have been identified in the BBB (Fig. 6.1b) (Loescher and
Potschka, 2005). The role of the transporters in the BBB has been extensively
investigated in transporter knockout mice. P-gp is highly expressed in the
luminal membrane of brain endothelia cells and plays a critical role in
restricting the passage of lipophilic compounds into the brain (Loescher and
Potschka, 2005). Antihistamines have found their greatest therapeutic potential
in the treatment and management of various allergic disorders, including
seasonal and perennial rhinitis, urticaria, and dermatological conditions
(Hindmarch, 2002). However, the most problematic aspect of their use is
sedation, which can severely compromise the safe performance of cognitive and
psychomotor tasks of everyday living. The third generation antihistamine drug
fexofenadine, which is a P-gp substrate (Tahara et al., 2005) and does not cross
the blood–brain barrier, has no objective evidence of sedation even at doses
two to three times those normally used for seasonal allergic rhinitis
(Hindmarch, 2002). Wolff et al. reported that imatinib (Gleevec, STI-571), a
potent and selective tyrosine kinase inhibitor, effectively controlled the
systemic proliferation of transduced bone marrow cells in mice, but many of
the mice unexpectedly developed progressive neurological deficit due to
leukemia infiltration of the brain and leptomeninges after 2–4 months although
imatinib has shown an effective inhibition on glioblastoma cell growth in
preclinicalin vitroandin vivostudies (Kilic et al., 2000), which suggested that
there was inadequate imatinib penetration of the drug into the central nervous
system (CNS) (Wolff et al., 2003). Imatinib concentrations in mouse
cerebrospinal fluid (CSF) were less than 1% than that in plasma (Wolff et
al., 2003). A limited penetration of imatinib into the brain was also observed
both preclinically and clinically (Pfeifer et al. 2003; Neville et al. 2004; Leis
et al., 2004). Both Mdr1(-/-) and Bcrp1(-/-) knockout mice demonstrated that
P-gp and Bcrp could limit imatinib brain penetration (Breedveld et al., 2005).
Thus, BCRP and P-gp inhibitors may improve delivery of imatinib to
malignant gliomas.
P-gp, BCRP, and MRPs are present in placenta and contribute to the
maternal–fetal barrier. Their role in restricting placenta penetration of drugs
can be demonstrated by using efflux transporter inhibitors and pregnant
transporter genetic knockout mice. With the pretreatment of GF120918 (an
inhibitor of both P-gp and BCRP) 2 h before intravenous administration of
topotecan to pregnant Mdr1a/1b(-/-) mice, the plasma levels of topotecan were
3.2- and 1.6-fold higher in fetuses and dams, respectively. These data suggest
that Bcrp1 plays an important role in protecting fetuses from potentially toxic
xenobiotics (Jonker et al., 2000).
ROLES OF TRANSPORTERS IN DRUG DISPOSITION AND TOXICITY 149