Compartment-specific roles of ATP-binding cassette transporters define differential topotecan distribution in brain parenchyma and cerebrospinal fluid.
Topotecan is a substrate of the ATP-binding cassette transporters P-glycoprotein (P-gp/MDR1) and breast cancer resistance protein (BCRP). To define the role of these transporters in topotecan penetration into the ventricular cerebrospinal fluid (vCSF) and brain parenchymal extracellular fluid (ECF) compartments, we performed intracerebral microdialysis on transporter-deficient mice after an intravenous dose of topotecan (4 mg/kg). vCSF penetration of unbound topotecan lactone was measured as the ratio of vCSF-to-plasma area under the concentration-time curves. The mean +/- SD ratios for wild-type, Mdr1a/b(-/-), Bcrp1(-/-), and Mdr1a/b(-/-)Bcrp1(-/-) mice were 3.07 +/- 0.09, 2.57 +/- 0.17, 1.63 +/- 0.12, and 0.86 +/- 0.05, respectively. In contrast, the ECF-to-plasma ratios for wild-type, Bcrp1(-/-), and Mdr1a/b(-/-)Bcrp1(-/-) mice were 0.36 +/- 0.06, 0.42 +/- 0.06, and 0.88 +/- 0.07. Topotecan lactone was below detectable limits in the ECF of Mdr1a/b(-/-) mice. When gefitinib (200 mg/kg) was preadministered to inhibit Bcrp1 and P-gp, the vCSF-to-plasma ratio decreased to 1.29 +/- 0.09 in wild-type mice and increased to 1.13 +/- 0.13 in Mdr1a/b(-/-)Bcrp1(-/-) mice, whereas the ECF-to-plasma ratio increased to 0.74 +/- 0.14 in wild-type and 1.07 +/- 0.03 in Mdr1a/b(-/-)Bcrp1(-/-) mice. Preferential active transport of topotecan lactone over topotecan carboxylate was shown in vivo by vCSF lactone-to-carboxylate area under the curve ratios for wild-type, Mdr1a/b(-/-), Bcrp1(-/-), and Mdr1a/b(-/-)Bcrp1(-/-) mice of 5.69 +/- 0.83, 3.85 +/- 0.64, 3.61 +/- 0.46, and 0.78 +/- 0.19, respectively. Our results suggest that Bcrp1 and P-gp transport topotecan into vCSF and out of brain parenchyma through the blood-brain barrier. These findings may help to improve pharmacologic strategies to treat brain tumors.
Shen
Jun
J
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105-2794, USA.
Carcaboso
Angel M
AM
Hubbard
K Elaine
KE
Tagen
Michael
M
Wynn
Henry G
HG
Panetta
John C
JC
Waters
Christopher M
CM
Elmeliegy
Mohamed A
MA
Stewart
Clinton F
CF
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000502:physiology; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000502:physiology*; D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics; D019540:Area Under Curve; D001692:Biological Transport / Q000187:drug effects; D001798:Blood Proteins / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D045744:Cell Line, Tumor; D000077156:Gefitinib; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D017551:Microdialysis; D011485:Protein Binding; D011799:Quinazolines / Q000494:pharmacology; D014018:Tissue Distribution; D019772:Topotecan / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D000097202:ATP-Binding Cassette Sub-Family B Member 4
D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D001798:Blood Proteins; D000077156:Gefitinib; D011799:Quinazolines; D019772:Topotecan; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C501412:Abcg2 protein, mouse; C095122:multidrug resistance protein 3