P-GLYCOPROTEIN-MEDIATED TRANSPORT OF ITRACONAZOLE ACROSS THE BLOOD-BRAIN-BARRIER

The mechanism for the accumulation of itraconazole (ITZ) in its elimin ation from the brain was studied in rats and mice, The concentration o f ITZ in liver tissue declined in parallel with the plasma ITZ concent ration 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 (K-p value) showed a marked overshooting, and the K-p value increased with increasing dose; those 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 effl uxes 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. The K-p value for the brain tis sue was significantly increased in the presence of ketoconazole or ver apamil. The brain K-p value for mdr1a knockout mice was also significa ntly increased compared with that of control mice. Moreover, the uptak e of vincristine Ok 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 b arrier; and ITZ can be an inhibitor of various substrates of P-gp.