Comparative bioavailability of the microemulsion formulation of cyclosporine (Neoral) with a generic dispersion formulation (Cicloral) in young healthy male volunteers

The aim of this study was to compare the bioavailability of cyclosporine (CyA) from the generic dispersion formulation Cicloral (CIC) with the microemulsion formulation Neoral (NEO) and the original Sandimmune (SIM) capsules after single doses of 100, 300, or 600 mg of drug, respectively. The study was performed according to an open 3-period cross-over design with 12 young healthy male volunteers for each dosage. The concentrations of CyA and its main metabolites were determined by high performance liquid chromatography in whole blood and urine up to 48 hours postdosing. Peak concentrations and area under the time-concentration curve were greater for the NEO and CIC formulations compared with SIM, and the mean bioavailability of CIC was significantly (P<0.05) lower compared with NEO. The bioavailability of SIM compared with NEO was 54% to 71%, in agreement with previous results. Bioequivalence was not demonstrated between CIC (test) and NEO (reference) as the 90% confidence intervals were outside the 80% to 125% guidelines based on log-transformed AUCs, and were 75.2% to 87.7% at 100 mg, 79.2% to 91.8% at 300 mg, and 76.6% to 94.5% at 600 mg doses. The respective values for Cmax were 78.9% to 94.6%, 80.7% to 95.0%, and 71.4% to 84.1%. A good correlation was demonstrated between the urinary recovery of CyA and the AUC4. Therefore, the urinary recovery of CyA may be helpful as a surrogate parameter for the systemic exposure of patients to CyA. Whereas the relative amount of hydroxylated metabolites (AM1, AM9, AM1c) was similar for all formulations and doses, the urinary recovery of the N-demethylated metabolite AM4N decreased with increasing dose indicating saturable metabolism. No relationship could be demonstrated between CYP3A activity using dextromethorphan as a probe for the metabolic clearance of CyA

Transport of paclitaxel (Taxol) across the blood-brain barrier in vitro and in vivo

Paclitaxel concentrations in the brain are very low after intravenous injection. Since paclitaxel is excluded from some tumors by p-glycoprotein (p-gp), the same mechanism may prevent entry into the brain. In vitro, paclitaxel transport was examined in capillaries from rat brains by confocal microscopy using BODIPY Fl-paclitaxel. Western blots and immunostaining demonstrated apical expression of p-gp in isolated endothelial cells, vessels, and tissue. Secretion of BODIPY Fl-paclitaxel into capillary lumens was specific and energy-dependent. Steady state luminal fluorescence significantly exceeded cellular fluorescence and was reduced by NaCN, paclitaxel, and SDZ PSC-833 (valspodar), a p-gp blocker. Leukotriene C(4) (LTC(4)), an Mrp2-substrate, had no effect. Luminal accumulation of NBDL-cyclosporin, a p-gp substrate, was inhibited by paclitaxel. In vivo, paclitaxel levels in the brain, liver, kidney, and plasma of nude mice were determined after intravenous injection. Co-administration of valspodar led to increased paclitaxel levels in brains compared to monotherapy. Therapeutic relevance was proven for nude mice with implanted intracerebral human U-118 MG glioblastoma. Whereas paclitaxel did not affect tumor volume, co-administration of paclitaxel (intravenous) and PSC833 (peroral) reduced tumor volume by 90%. Thus, p-gp is an important obstacle preventing paclitaxel entry into the brain, and inhibition of this transporter allows the drug to reach sensitive tumors within the CNS