Effect of Efflux Inhibition on Brain Uptake of Itraconazole in Mice Infected withCryptococcus neoformans

Abstract

This article is available online at http://dmd.aspetjournals.org 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.

Tissue Penetration of Antifungal Agents

“…tein (75); variable oral bioavailability, e.g., of itraconazole (47) and posaconazole (228); and interpatient variability in clearance, e.g., of voriconazole (48).…”

Development and lyophilization of itraconazole loaded poly(butylcyanoacrylate) nanospheres as a drug delivery system

“…In these studies itraconazole had only a low or no potential to inhibit P-glycoprotein (Hsiao et al, 2008;Sugimoto et al, 2011). Also Imbert et al showed that inhibiting P-glycoprotein led to an increased itraconazole uptake (Imbert et al, 2003). These results verify the fact that ITZ is a P-glycoprotein substrate and this fact hampers the efficacy of ITZ therapy of cryptococcal meningitis.…”

Human Pharmacogenomic Variations and Their Implications for Antifungal Efficacy

“…Furthermore, the brain/plasma itraconazole ratio is significantly increased in the presence of the P-gp inhibitors verapamil and ketoconazole, suggesting that P-gp in the brain capillary endothelial cells participates in a process of active efflux of itraconazole from the brain to the blood at the BBB. In addition, GF-120918 (a P-gp inhibitor) in pretreated mice significantly increased the cerebral itraconazole AUC compared to that of untreated mice infected with Cryptococcus neoformans (130). Preclinical studies indicated that caspofungin is not a substrate of P-gp, although the caspofungin AUC is reduced by 20% with coadministration of rifampin, efavirenz, phenytoin, nevirapine, dexamethasone, and carbamazepamine and increased by 35% with coadministration of cyclosporine (65), compounds which are transported by P-gp and MRPs (226).…”

“…Itraconazole (4) and ketoconazole, but not fluconazole, miconazole, and amphotericin B, inhibit P-gp function; in fact, this approach has been undertaken to reverse the anticancer resistance of human leukemia cells in vitro (129). However, antifungal agents could also work as substrates of P-gp, given that P-gp mediates the transport of itraconazole across the blood-brain barrier (BBB) and the similarities between P-gp substrates and CYP3A4 substrates/ inhibitors, such as itraconazole, fluconazole, and ketoconazole (130,187,195). Furthermore, fluconazole resistance in Candida albicans has been associated with overexpression of C. albicans MDR1, an ortholog of the human ABCB1 gene (276).…”