title: Topotecan central nervous system penetration is altered by a tyrosine kinase inhibitor.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, University of Tennessee Health Science Center, Memphis, Tennessee 38105, USA.
authors.forename: Yanli
authors.initials: Y
authors.lastname: Zhuang
authors.forename: Charles H
authors.initials: CH
authors.lastname: Fraga
authors.forename: K Elaine
authors.initials: KE
authors.lastname: Hubbard
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Hagedorn
authors.forename: John C
authors.initials: JC
authors.lastname: Panetta
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Waters
authors.forename: Clinton F
authors.initials: CF
authors.lastname: Stewart
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000284:Administration, Oral; D000465:Algorithms; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D019540:Area Under Curve; D001798:Blood Proteins / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002490:Central Nervous System / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D045604:Extracellular Fluid / Q000378:metabolism; D005260:Female; D000077156:Gefitinib; D007150:Immunohistochemistry; D007275:Injections, Intravenous; D051379:Mice; D008810:Mice, Inbred C57BL; D017551:Microdialysis; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors; D019772:Topotecan / Q000134:cerebrospinal fluid / Q000378:metabolism / Q000493:pharmacokinetics*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C501412:Abcg2 protein, mouse; D000970:Antineoplastic Agents; D001798:Blood Proteins; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D019772:Topotecan; D000077156:Gefitinib