ivermectin, loperamide and UK-224671 (P-gp substrates (Chen et al., 2003a)),
as well as topotecan, nitrofurantoin, ME-3229, GV-196771, and sulfasalazine
(BCRP substrates) (Xia et al., 2005b; Zaher et al., 2006). Sparreboom et al.
have used Mdr1a(-/-) mice to demonstrate the effect of gut P-gp on the
pharmacokinetics of paclitaxel (Sparreboom et al., 1997). The area under the
plasma concentration time curves (AUC) was two- and six-fold higher in
Mdr1a(-/-) mice than in wt mice after IV and oral drug administration,
respectively. Consequently, the oral bioavailability in mice receiving 10 mg
paclitaxel per kg body weight increased from only 11% in wt mice to 35% in
Mdr1a(-/-) mice. The cumulative fecal excretion (0–96 h) was markedly
reduced from 40% (after IV administration) to 87% (after oral administration)
of the administered dose in wt mice to below 3% in Mdr1a(-/-) mice. Biliary
Intenstine
Blood
Blood Blood
Blood Lumen Lumen
Lumen Lumen
MDR1
MDR1,3
MDR1
MDR1
BCRP BCRP
BCRP
MRP1
MRP1
MRP3 MRP1
MRP2
MRP
MRP4
MRP
MRP2
MRP3
OATP2
OATP3
OATP
OATP
OATP
OATP2
OAT4
OAT
OAT
OAT3
OAT2
OCT
OCT2
OCT1
BSEP
NTCP
B,C,8
ASBT
MCT
MCT
PEPT1
Glucose
Amino Glucose
acid Amino
Acid
(a) (b)
(c) (d)
BBB
Liver Kidney
4,5
NT
1,2,3
4C1
2,4
1,2
OCTN
PEPT
Na+ 1,2
FIGURE 6.1 Localization of transporters in intestinal enterocytes, brain endothelial
cells, hepatocytes and kidney tubular epithelial cells.
ROLES OF TRANSPORTERS IN DRUG DISPOSITION AND TOXICITY 147