Cremophor EL releases cyclosporin A adsorbed on blood cells and blood vessels, and increases apparent plasma concentration of cyclosporin A

We examined the influence of cremophor EL (crEL) on the disposition kinetics of CyA in rats. A dose of 10 mg/kg of CyA in a volume of 750 μL containing 4.3, 16 or 30% concentration of crEL was intravenously administered over 1 min to rats. The values of distribution volume at the steady-state (Vdss) and total clearance (CLtot) of CyA in the presence of increasing amounts of crEL were decreased to about 1/3-1/5 of those with 4.3% crEL, in a crEL concentration-dependent manner. The values of blood to plasma concentration ratio (RBP) and the apparent tissue to plasma concentration ratio (Kp,app) of CyA with 30% crEL were both only about 1/2 of those of CyA with 4.3% crEL. Next, rats were intravenously given 30% crEL solution at 30 min after an intravenous administration of CyA (10 mg/kg) with 4.3% crEL. Subsequently, the blood and plasma concentrations of CyA rose significantly to 2.4 and 4.7 times those seen when i.v. 30% crEL was not given, respectively. In an in vitro study, we found that the uptake of CyA by red blood cells is inhibited by crEL, and that CyA adsorbed on the inner surface of blood vessels after the administration of CyA is released by crEL. The disposition kinetics of CyA is altered by i.v. administration in combination with the surfactant vehicle crEL, in a crEL concentration-dependent manner.