Pharmacokinetics of kadsurenone and its interaction with cyclosporin A in rats using a combined HPLC and microdialysis system.

Kadsurenone is a neolignan with specific antagonistic activity of platelet-activating factor, and is derived from the stems of Piper kadsura. To investigate the mechanism of hepatobiliary excretion of kadsurenone and its association with P-glycoprotein (P-gp), and to explore whether the hepatobiliary excretion of kadsurenone was associated with P-gp, a microdialysis system coupled with HPLC was developed to measure free-form kadsurenone in rat blood and bile. This study design was parallel in the following groups: six rats received kadsurenone alone (20 and 30 mg/kg, i.v.) as control group and the treated-group rats were co-administered with kadsurenone and CsA; P-gp inhibitor. The microdialysis probes were respectively inserted into the jugular vein toward right atrium and bile duct of male Sprague-Dawley rats for blood and bile sampling. CsA (20mg/kg) was administered 10 min prior to kadsurenone administration through the femoral vein and the collected samples were analyzed by a HPLC system. The analytes were separated by a C18 column (150 x 4.6 mm I.D., 5 microm) with a mobile phase of acetonitrile-water (50:50, v/v) at a flow-rate of 1 mL/min. The UV detection wavelength was set 235 nm. The calibration curve was linear over the concentration range of 0.05-10 microg/mL with the coefficient of determination of 0.997. The inter- and intra-assay accuracy and precision of the method ranged from -9.53% to 6.75%. The limit of detection and the limit of quantification were 0.01 and 0.05 microg/mL, respectively. The hepatobiliary excretion ratio of kadsurenone was defined by dividing the values of the area under the drug concentration curve (AUC) for bile and blood (AUC(bile)/AUC(blood)). The results indicated that the hepatobiliary excretion ratio of kadsurenone on the CsA treated-group was 1.2+/-0.1, which was not significantly different from the group of kadsurenone alone (1.3+/-0.2). This fact indicates that kadsurenone went through hepatobiliary excretion but might not be regulated by P-gp.

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 5-5000ng/mL range, with coefficients of correlation greater than 0.995. The limit of quantification for doxorubicin was 5ng/mL. This study was divided into the following four groups: DOX alone, DOX+CsA, Lipo-Dox alone and Lipo-Dox+CsA. After administering DOX (5mg/kg, i.v.) alone and DOX+CsA (10mg/kg, i.v.), it was undetectable in various brain regions. When the same dose of Lipo-Dox (5mg/kg, i.v.) and Lipo-Dox+CsA (10mg/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.