Topotecan central nervous system penetration is altered by a tyrosine kinase inhibitor.

Topotecan central nervous system penetration is altered by a tyrosine kinase inhibitor. Research Abstract Details 

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Topotecan central nervous system penetration is altered by a tyrosine kinase inhibitor. Abstract Text:

Yanli Zhuang,Charles H Fraga,K Elaine Hubbard,Nikolaus Hagedorn,John C Panetta,Christopher M Waters,Clinton F Stewart,

A potential strategy to increase the efficacy of topotecan to treat central nervous system (CNS) malignancies is modulation of the activity of ATP-binding cassette (ABC) transporters at the blood-brain and blood-cerebrospinal fluid barriers to enhance topotecan CNS penetration. This study focused on topotecan penetration into the brain extracellular fluid (ECF) and ventricular cerebrospinal fluid (CSF) in a mouse model and the effect of modulation of ABC transporters at the blood-brain and blood-cerebrospinal fluid barriers by a tyrosine kinase inhibitor (gefitinib). After 4 and 8 mg/kg topotecan i.v., the brain ECF to plasma AUC ratio of unbound topotecan lactone was 0.21 +/- 0.04 and 0.61 +/- 0.16, respectively; the ventricular CSF to plasma AUC ratio was 1.18 +/- 0.10 and 1.30 +/- 0.13, respectively. To study the effect of gefitinib on topotecan CNS penetration, 200 mg/kg gefitinib was administered orally 1 hour before 4 mg/kg topotecan i.v. The brain ECF to plasma AUC ratio of unbound topotecan lactone increased by 1.6-fold to 0.35 +/- 0.04, which was significantly different from the ratio without gefitinib (P < 0.05). The ventricular CSF to plasma AUC ratio significantly decreased to 0.98 +/- 0.05 (P < 0.05). Breast cancer resistance protein 1 (Bcrp1), an efficient topotecan transporter, was detected at the apical aspect of the choroid plexus in FVB mice. In conclusion, topotecan brain ECF penetration was lower compared with ventricular CSF penetration. Gefitinib increased topotecan brain ECF penetration but decreased the ventricular CSF penetration. These results are consistent with the possibility that expression of Bcrp1 and P-glycoprotein at the apical side of the choroid plexus facilitates an influx transport mechanism across the blood-cerebrospinal fluid barrier, resulting in high topotecan CSF penetration.

Topotecan central nervous system penetration is altered by a tyrosine kinase inhibitor. Publishing Authors By Initials

Y Zhuang,CH Fraga,KE Hubbard,N Hagedorn,JC Panetta,CM Waters,CF Stewart,

For similar heterocyclic compounds: alkaloids: camptothecin: topotecan research abstracts see: heterocyclic compounds: alkaloids: camptothecin: topotecan research

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MEDLINE DATE:

Topotecan central nervous system penetration is altered by a tyrosine kinase inhibitor. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Cancer research

VOLUME: 66

Page Numbers: 11305-13

Journal Abbreviation: Cancer Res.

ISSN: 0008-5472

DAY: 1

MONTH: Dec

YEAR: 2006

Topotecan central nervous system penetration is altered by a tyrosine kinase inhibitor. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 2984705

Topotecan central nervous system penetration is altered by a tyrosine kinase inhibitor. Keywords Mesh Terms:

KEYWORDS: Topotecan

MESH TERMS: pharmacokinetics

Chemical & Substance for Abstract: Topotecan central nervous system penetration is altered by a tyrosine kinase inhibitor. Information

Substance Name: gefitinib

Registry Number: 184475-35-2

Grant and Affiliation Information for Topotecan central nervous system penetration is altered by a tyrosine kinase inhibitor.

AFFILIATION: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, University of Tennessee Health Science Center, Memphis, Tennessee 38105, USA.

Country: United States

AGENCY: United States NIGMS

GRANT: GM071321

ACRONYM: GM

MEDLINETA: Cancer Res

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