cell. The gene nomenclature, protein name, tissue distribution, driven force,
substrate properties and the substrates, inhibitors and inducers of the common
drug-related transporters are listed in Table 6.1 (Haimeur et al., 2004; Kong
et al., 2004; Xia et al., 2005b).
6.2 ROLES OF TRANSPORTERS IN DRUG
DISPOSITION AND TOXICITY
Transporter proteins affect drug absorption in small intestine and drug
elimination in liver and/or kidney by governing drug substance in and out of
the intestinal enterocytes, hepatocytes, or renal tubular cells. Transporters can
also limit or facilitate penetration of drugs into brain, placenta, tumor, T-cells,
and others. The inhibition or lack of transporter functions can alter the
exposure of drugs to tissues and potentially result in either lack of efficacy or
increased toxicity, a classic example of this is provided by studies on
antiparasitic agent avermectin that caused neurotoxicity in CF-1 mice deficient
in P-gp (Lankas et al., 1997). The roles of transporters in drug disposition have
been evaluated by using transporter knockout or deficient animals or by using
transporter inhibitors in both animals and humans. The localizations of major
transporters in human intestine, liver, kidney, and brain are illustrated in
Fig. 6.1.
6.2.1 Transporters in Drug Absorption
Drug efflux transporters of the ABC family can restrict drug absorption by
pumping drugs out of intestinal epithelial cells. Of the known ABC drug efflux
transporters, P-glycoprotein, localized on the mucosal membrane of intestines,
is well documented for its involvement in oral drug absorptions.
Immunohistological studies showed high P-gp protein levels on the apical
surface of columnar epithelial cells but not in crypt cells in human jejunum and
colon (Thiebaut et al., 1987). The mRNA expression of P-gp increased
longitudinally along the gastrointestinal (GI) tract in humans (stomach<
duodenum<jejunum/ileum<colon) (Fojo et al., 1987; Thoern et al., 2005).
Similar to P-gp, strong staining of BCRP was observed on the luminal surface
of the intestine (Jonker et al., 2000). However, BCRP mRNA expression was
maximal in human duodenum and decreased continuously down to the rectum
(terminal ileum 93.7%, ascending colon 75.8%, transverse colon 66.6%,
descending colon 62.8%, and sigmoid colon 50.1%, as compared to the level in
duodenum) (Gutmann et al., 2005). The role of P-gp or BCRP in limiting
xenobiotics absorption has been directly evident in Mdr1a/1b (/)or
Bcrp1(-/-) mice (Chen et al., 2003a; Xia et al., 2005a). By comparing the oral
drug exposure in wild type (wt) mice and knockout mice, P-gp and Bcrp1 have
been shown to play major roles in the reduction of absorption such as of
several HIV protease inhibitors, topotecan, etoposide, tacrolimus, paclitaxel,
ROLES OF TRANSPORTERS IN DRUG DISPOSITION AND TOXICITY 139