PT - JOURNAL ARTICLE AU - Frédéric Imbert AU - Méryam Jardin AU - Christine Fernandez AU - Jean Charles Gantier AU - Françoise Dromer AU - Gabriel Baron AU - France Mentre AU - Ludy van Beijsterveldt AU - Eric Singlas AU - François Gimenez TI - Effect of Efflux Inhibition on Brain Uptake of Itraconazole in Mice Infected with <em>Cryptococcus neoformans</em> AID - 10.1124/dmd.31.3.319 DP - 2003 Mar 01 TA - Drug Metabolism and Disposition PG - 319--325 VI - 31 IP - 3 4099 - http://dmd.aspetjournals.org/content/31/3/319.short 4100 - http://dmd.aspetjournals.org/content/31/3/319.full SO - Drug Metab Dispos2003 Mar 01; 31 AB - 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 ofCryptococcus 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. The American Society for Pharmacology and Experimental Therapeutics