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
IntenstineBloodBlood BloodBlood Lumen LumenLumen Lumen
MDR1MDR1,3MDR1MDR1BCRP BCRPBCRPMRP1MRP1
MRP3 MRP1
MRP2
MRPMRP4MRPMRP2MRP3OATP2
OATP3OATPOATPOATP
OATP2OAT4OATOAT
OAT3OAT2OCTOCT2OCT1BSEP
NTCPB,C,8ASBT
MCTMCTPEPT1
Glucose
Amino Glucose
acid Amino
Acid(a) (b)(c) (d)BBBLiver Kidney4,5
NT1,2,34C12,41,2OCTNPEPT
Na+ 1,2FIGURE 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