title: Effect of efflux inhibition on brain uptake of itraconazole in mice infected with Cryptococcus neoformans.
abstract: Itraconazole is a fungistatic agent that, although highly lipophilic, shows poor transport through the blood brain barrier that may be due to efflux proteins. The combined administration of an efflux inhibitor with itraconazole should increase cerebral itraconazole concentrations and therefore, improve the treatment of Cryptococcus neoformans meningitis with this antifungal agent. To test this hypothesis, we have studied the influence of murine cerebral infection with C. neoformans and the inhibition of efflux by intraperitoneal injection of a P-glycoprotein inhibitor, GF120918 [N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)-ethyl]-phenyl)9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide], on the pharmacokinetics of itraconazole in plasma and brain after a single intraperitoneal itraconazole injection. We also investigated the influence of efflux inhibition on the efficacy of repeated doses of itraconazole in this murine model. The results showed that in healthy and infected mice pretreated or not with GF120918, plasma itraconazole values of area under the curve (AUC) were similar. In contrast, cerebral values of AUC were higher in infected mice compared with healthy mice. Moreover, the pretreatment of infected mice with GF120918 significantly increased cerebral itraconazole values of area under the curve and decreased weight loss in the treatment with itraconazole of a cerebral infection with C. neoformans.
authors.affiliation: Département de Pharmacie Clinique, Faculté de Pharmacie, Châtenay-Malabry, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Imbert
authors.forename: Méryam
authors.initials: M
authors.lastname: Jardin
authors.forename: Christine
authors.initials: C
authors.lastname: Fernandez
authors.forename: Jean Charles
authors.initials: JC
authors.lastname: Gantier
authors.forename: Françoise
authors.initials: F
authors.lastname: Dromer
authors.forename: Gabriel
authors.initials: G
authors.lastname: Baron
authors.forename: France
authors.initials: F
authors.lastname: Mentre
authors.forename: Ludy
authors.initials: L
authors.lastname: Van Beijsterveldt
authors.forename: Eric
authors.initials: E
authors.lastname: Singlas
authors.forename: François
authors.initials: F
authors.lastname: Gimenez
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000166:Acridines / Q000494:pharmacology; D000818:Animals; D000935:Antifungal Agents / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000382:microbiology*; D003453:Cryptococcosis / Q000188:drug therapy / Q000378:metabolism*; D003455:Cryptococcus neoformans / Q000187:drug effects; D007546:Isoquinolines / Q000494:pharmacology; D017964:Itraconazole / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D021381:Protein Transport / Q000187:drug effects; D044005:Tetrahydroisoquinolines
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000166:Acridines; D000935:Antifungal Agents; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; D017964:Itraconazole; C083501:Elacridar