P-Glycoprotein-Mediated Transport of Itraconazole across the Blood-Brain Barrier

Abstract

The mechanism for the accumulation of itraconazole (ITZ) in its elimination from the brain was studied in rats and mice. The concentration of ITZ in liver tissue declined in parallel with the plasma ITZ concentration until 24 h after intravenous injection of the drug (half-life, 5 h); however, the ITZ in brain tissue rapidly disappeared (half-life, 0.4 h). The time profiles of the brain/plasma ITZ concentration ratio (Kp value) showed a marked overshooting, and the Kp value increased with increasing dose; these phenomena were not observed in the liver tissue. This finding indicates the occurrence of a nonlinear efflux of ITZ from the brain to the blood. Moreover, based on a pharmacokinetic model which hypothesized processes for both nonlinear and linear effluxes of ITZ from the brain to the blood, we found that the efflux rate constant in the saturable process was approximately sevenfold larger than that in the nonsaturable process. TheKp value for the brain tissue was significantly increased in the presence of ketoconazole or verapamil. The brainKp value for mdr1a knockout mice was also significantly increased compared with that of control mice. Moreover, the uptake of vincristine or vinblastine, both of which are substrates of the P glycoprotein (P-gp), into mouse brain capillary endothelial cells was also significantly increased by ITZ or verapamil. In conclusion, P-gp in the brain capillary endothelial cells participates in a process of active efflux of ITZ from the brain to the blood at the blood-brain barrier, and ITZ can be an inhibitor of various substrates of P-gp.

Role of P-glycoprotein in Limiting the Brain Penetration of Glabridin, An Active Isoflavan from the Root of Glycyrrhiza glabra

“…The V max1 and V max2 for vinblastine uptake by RBMVECs were 7.37 T 1.16 and 3.11 T 0.21 ng/min/mg cellular protein, respectively. These results are comparable to those reported in the literature (43,44). We also monitored the intracellular concentration of glabridin at 1.0 mM upon incubation over 120 min (Fig.…”

Characteristic biological effects of itraconazole on L929 fibroblasts and their cell membrane

“…4). Since it has been reported that ITCZ is an inhibitor of P-glycoprotein, 13 and that the inhibition of P-glycoprotein enhances the cytotoxicity of VCR in leukemic cells, 14 this enhanced VCR activity may be explained by the possible accumulation of VCR in the cells, resulting from P-glycoprotein inhibition.…”

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

“…One reason could be a low permeation of itraconazole across the blood brain barrier (BBB) after its oral administration, which was already observed in vivo with rats and mice using itraconazole capsules containing polyethylene glycol (Perfect et al, 1986). Another reason for therapeutic failures in cryptococcal meningitis could be the rapid transport of itraconazole out of the brain as shown in a study in which itraconazole was administered intravenously in a polyethylene glycol-containing solution (Miyama et al, 1998). Miyama et al suggested that itraconazole is a substrate for multi-drug resistance gene P-glycoprotein expressed in the mouse brain endothelial cells and may be a cause for rapid efflux of itraconazole from the brain tissue.…”