title: Irinotecan and temozolomide brain distribution: a focus on ABCB1.
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.
authors.affiliation: Clinical Pharmacy Department - EA 4123, College of Pharmacy, Paris-Sud University, 5 rue Jean Baptiste Clement, 92296, Chatenay Malabry, France, lauriane.goldwirt@u-psud.fr.
authors.forename: Lauriane
authors.initials: L
authors.lastname: Goldwirt
authors.forename: Kevin
authors.initials: K
authors.lastname: Beccaria
authors.forename: Alexandre
authors.initials: A
authors.lastname: Carpentier
authors.forename: Robert
authors.initials: R
authors.lastname: Farinotti
authors.forename: Christine
authors.initials: C
authors.lastname: Fernandez
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D001692:Biological Transport / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D005260:Female; D006207:Half-Life; D007274:Injections, Intraperitoneal; D000077146:Irinotecan; D051379:Mice; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D011355:Prodrugs / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D000077204:Temozolomide; D014018:Tissue Distribution; D059004:Topoisomerase I Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D018906:Antineoplastic Agents, Alkylating; D000972:Antineoplastic Agents, Phytogenic; D009419:Nerve Tissue Proteins; D011355:Prodrugs; D059004:Topoisomerase I Inhibitors; D000077146:Irinotecan; D003606:Dacarbazine; C095122:multidrug resistance protein 3; D002166:Camptothecin; D000077204:Temozolomide