Role of breast cancer resistance protein in the bioavailability and fetal penetration of topotecan.
METHODS
Breast cancer resistance protein (BCRP/MXR/ABCP) is a multidrug-resistance protein that is a member of the adenosine triphosphate-binding cassette family of drug transporters. BCRP can render tumor cells resistant to the anticancer drugs topotecan, mitoxantrone, doxorubicin, and daunorubicin. To investigate the physiologic role of BCRP, we used polarized mammalian cell lines to determine the direction of BCRP drug transport. We also used the BCRP inhibitor GF120918 to assess the role of BCRP in protecting mice against xenobiotic drugs. Bcrp1, the murine homologue of BCRP, was expressed in the polarized mammalian cell lines LLC-PK1 and MDCK-II, and the direction of Bcrp1-mediated transport of topotecan and mitoxantrone was determined. To avoid the confounding drug transport provided by P-glycoprotein (P-gp), the roles of Bcrp1 in the bioavailability of topotecan and the effect of GF120918 were studied in both wild-type and P-gp-deficient mice and their fetuses.


RESULTS
Bcrp1 mediated apically directed transport of drugs in polarized cell lines. When both topotecan and GF120918 were administered orally, the bioavailability (i.e., the extent to which a drug becomes available to a target tissue after administration) of topotecan in plasma was dramatically increased in P-gp-deficient mice (greater than sixfold) and wild-type mice (greater than ninefold), compared with the control (i.e., vehicle-treated) mice. Furthermore, treatment with GF120918 decreased plasma clearance and hepatobiliary excretion of topotecan and increased (re-)uptake by the small intestine. In pregnant GF120918-treated, P-gp-deficient mice, relative fetal penetration of topotecan was twofold higher than that in pregnant vehicle-treated mice, suggesting a function for BCRP in the maternal-fetal barrier of the placenta.


CONCLUSIONS
Bcrp1 mediates apically directed drug transport, appears to reduce drug bioavailability, and protects fetuses against drugs. We propose that strategic application of BCRP inhibitors may thus lead to more effective oral chemotherapy with topotecan or other BCRP substrate drugs.
Jonker
J W
JW
Division of Experimental Therapy, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Smit
J W
JW
Brinkhuis
R F
RF
Maliepaard
M
M
Beijnen
J H
JH
Schellens
J H
JH
Schinkel
A H
AH
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D000166:Acridines / Q000008:administration & dosage / Q000494:pharmacology*; D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D018076:DNA, Complementary / Q000032:analysis; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics; D005260:Female; D005333:Fetus / Q000187:drug effects*; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects; D007546:Isoquinolines / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008942:Mitoxantrone / Q000097:blood / Q000493:pharmacokinetics*; D009363:Neoplasm Proteins; D010920:Placenta / Q000187:drug effects; D011247:Pregnancy; D012333:RNA, Messenger / Q000032:analysis; D044005:Tetrahydroisoquinolines; D019772:Topotecan / Q000097:blood / Q000493:pharmacokinetics*
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000166:Acridines; D000970:Antineoplastic Agents; D018076:DNA, Complementary; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D044005:Tetrahydroisoquinolines; D019772:Topotecan; D008942:Mitoxantrone; C083501:Elacridar