Abstract
Glioblastoma (GBM), the most common primary brain tumor in adults, is usually rapidly fatal with median survival duration of only 15 months and a 3-year survival rate of <7 %. Temozolomide (TMZ) is the only anticancer drug that has improved survival in GBM when administered with concomitant radiotherapy. Irinotecan (CPT-11) has also shown efficacy in recurrent gliomas monotherapy with moderate response. As the efficacy of GBM treatments relies on their brain distribution through the blood-brain barrier (BBB), the aim of the present work was to study, on an in vivo model, the brain distribution of TMZ, CPT-11 and its active metabolite, SN-38. We have focussed on the role of ABCB1, the main efflux transporter at the BBB level, through pharmacokinetics studies in CF1 mdr1a(+/+) and mdr1a(-/-) mice. Our results show that TMZ, CPT-11 and SN-38 are transported by ABCB1 at the BBB level with brain/plasma ratios of 1.1, 2.1 and 2.3, respectively.
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B / genetics
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ATP Binding Cassette Transporter, Subfamily B / metabolism*
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Animals
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Antineoplastic Agents, Alkylating / administration & dosage
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Antineoplastic Agents, Alkylating / blood
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Antineoplastic Agents, Alkylating / metabolism
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Antineoplastic Agents, Alkylating / pharmacokinetics*
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Antineoplastic Agents, Phytogenic / administration & dosage
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Antineoplastic Agents, Phytogenic / blood
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Antineoplastic Agents, Phytogenic / metabolism
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Antineoplastic Agents, Phytogenic / pharmacokinetics
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Biological Transport / drug effects
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Blood-Brain Barrier / drug effects
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Blood-Brain Barrier / metabolism*
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Brain / drug effects
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Brain / metabolism*
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Camptothecin / administration & dosage
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Camptothecin / analogs & derivatives*
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Camptothecin / blood
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Camptothecin / metabolism
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Camptothecin / pharmacokinetics
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Dacarbazine / administration & dosage
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Dacarbazine / analogs & derivatives*
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Dacarbazine / blood
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Dacarbazine / metabolism
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Dacarbazine / pharmacokinetics
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Female
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Half-Life
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Injections, Intraperitoneal
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Irinotecan
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Mice
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Mice, Inbred Strains
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Mice, Mutant Strains
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism
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Neurons / drug effects
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Neurons / metabolism
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Prodrugs / administration & dosage
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Prodrugs / metabolism
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Prodrugs / pharmacokinetics
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Temozolomide
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Tissue Distribution
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Topoisomerase I Inhibitors / administration & dosage
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Topoisomerase I Inhibitors / blood
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Topoisomerase I Inhibitors / metabolism
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Topoisomerase I Inhibitors / pharmacokinetics*
Substances
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ATP Binding Cassette Transporter, Subfamily B
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Antineoplastic Agents, Alkylating
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Antineoplastic Agents, Phytogenic
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Nerve Tissue Proteins
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Prodrugs
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Topoisomerase I Inhibitors
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Irinotecan
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Dacarbazine
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multidrug resistance protein 3
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Camptothecin
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Temozolomide