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

Jun Shen, Angel M. Carcaboso, K. Elaine Hubbard, Michael Tagen, Henry G. Wynn, John C. Panetta, Christopher Waters, Mohamed A. Elmeliegy, Clinton F. Stewart

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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.Prefer ential 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.

Original languageEnglish (US)
Pages (from-to)5885-5892
Number of pages8
JournalCancer Research
Volume69
Issue number14
DOIs
StatePublished - Jul 15 2009

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Topotecan
ATP-Binding Cassette Transporters
Cerebrospinal Fluid
Extracellular Fluid
Brain
Lactones
Active Biological Transport
Microdialysis
P-Glycoprotein
Blood-Brain Barrier
Brain Neoplasms
Area Under Curve
Breast Neoplasms

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Compartment-specific roles of ATP-binding cassette transporters define differential topotecan distribution in brain parenchyma and cerebrospinal fluid. / Shen, Jun; Carcaboso, Angel M.; Hubbard, K. Elaine; Tagen, Michael; Wynn, Henry G.; Panetta, John C.; Waters, Christopher; Elmeliegy, Mohamed A.; Stewart, Clinton F.

In: Cancer Research, Vol. 69, No. 14, 15.07.2009, p. 5885-5892.

Research output: Contribution to journalArticle

Shen, J, Carcaboso, AM, Hubbard, KE, Tagen, M, Wynn, HG, Panetta, JC, Waters, C, Elmeliegy, MA & Stewart, CF 2009, 'Compartment-specific roles of ATP-binding cassette transporters define differential topotecan distribution in brain parenchyma and cerebrospinal fluid', Cancer Research, vol. 69, no. 14, pp. 5885-5892. https://doi.org/10.1158/0008-5472.CAN-09-0700
Shen, Jun ; Carcaboso, Angel M. ; Hubbard, K. Elaine ; Tagen, Michael ; Wynn, Henry G. ; Panetta, John C. ; Waters, Christopher ; Elmeliegy, Mohamed A. ; Stewart, Clinton F. / Compartment-specific roles of ATP-binding cassette transporters define differential topotecan distribution in brain parenchyma and cerebrospinal fluid. In: Cancer Research. 2009 ; Vol. 69, No. 14. pp. 5885-5892.
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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.Prefer ential 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.",
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AU - Shen, Jun

AU - Carcaboso, Angel M.

AU - Hubbard, K. Elaine

AU - Tagen, Michael

AU - Wynn, Henry G.

AU - Panetta, John C.

AU - Waters, Christopher

AU - Elmeliegy, Mohamed A.

AU - Stewart, Clinton F.

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N2 - 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.Prefer ential 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.

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