Compartment-specific roles of ATP-binding cassette transporters define differential topotecan distribution in brain parenchyma and cerebrospinal fluid.

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Shen J, Carcaboso AM, Hubbard KE, Tagen M, Wynn HG, Panetta JC, Waters CM, Elmeliegy MA, Stewart CF

Compartment-specific roles of ATP-binding cassette transporters define differential topotecan distribution in brain parenchyma and cerebrospinal fluid.

Cancer Res. 2009 Jul 15;69(14):5885-92. doi: 10.1158/0008-5472.CAN-09-0700. Epub 2009 Jun 30.

PubMed ID

19567673 [ View in PubMed

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Abstract

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.

DrugBank Data that Cites this Article

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Gefitinib	ATP-binding cassette sub-family G member 2	Protein	Humans	Unknown	Substrate Inhibitor	Details
Gefitinib	P-glycoprotein 1	Protein	Humans	Unknown	Substrate Inhibitor	Details
Topotecan	ATP-binding cassette sub-family G member 2	Protein	Humans	Unknown	Substrate	Details
Topotecan	P-glycoprotein 1	Protein	Humans	Unknown	Substrate	Details