RT Journal Article SR Electronic T1 Effect of Efflux Inhibition on Brain Uptake of Itraconazole in Mice Infected with Cryptococcus neoformans JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 319 OP 325 DO 10.1124/dmd.31.3.319 VO 31 IS 3 A1 Frédéric Imbert A1 Méryam Jardin A1 Christine Fernandez A1 Jean Charles Gantier A1 Françoise Dromer A1 Gabriel Baron A1 France Mentre A1 Ludy van Beijsterveldt A1 Eric Singlas A1 François Gimenez YR 2003 UL http://dmd.aspetjournals.org/content/31/3/319.abstract 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