Effect of cyclosporin A on the brain regional distribution of doxorubicin in rats

Doxorubicin (DOX) is an anthracycline antibiotic that possesses broad-spectrum antineoplastic activity, and is one of the most important anticancer agents. The purpose of this study was to investigate the effects of cyclosporine A (CsA) on the brain regional distribution of DOX and its liposome DOX formulation (Lipo-Dox). Liquid chromatography with tandem mass spectrometry (LC–MS/MS) was used to measure DOX in rat plasma and in various brain regions (cerebral cortex, hippocampus, striatum, midbrain, cerebellum, and the rest of brain). Good linearity was achieved over the 5–5000 ng/mL range, with coefficients of correlation greater than 0.995. The limit of quantification for doxorubicin was 5 ng/mL. This study was divided into the following four groups: DOX alone, DOX + CsA, Lipo-Dox alone and Lipo-Dox + CsA. After administering DOX (5 mg/kg, i.v.) alone and DOX + CsA (10 mg/kg, i.v.), it was undetectable in various brain regions. When the same dose of Lipo-Dox (5 mg/kg, i.v.) and Lipo-Dox + CsA (10 mg/kg, i.v.) were given individually, the plasma level and the brain regional level of DOX were much greater than those of DOX given alone. These results indicate that Lipo-Dox prolongs the DOX level in plasma and enhances brain distribution of DOX. The disposition of DOX might be regulated by P-glycoprotein.