Enhanced absorption of cyclosporin A by complexation with dimethyl-beta-cyclodextrin in bile duct-cannulated and -noncannulated rats

The enhancing effects of dimethyl-beta-cyclodextrin (DM-beta-CyD) on the ab sorption of cyclosporin A (CsA) after oral administration to rats under bil e duct-cannulated and -noncannulated conditions ere investigated. The disso lution rate of CsA was markedly augmented by complexation with DM-beta-CyD. In a closed loop in situ study, DM-beta-CyD considerably increased the cum ulative amounts of CsA in the mesenteric venous blood after injection of th e aqueous CsA suspension into the small intestinal sac of rats. In addition , the cumulative amount ratio of M1, the dominant metabolite of CsA in rats , to CsA in the mesenteric venous blood for up to 40 min after the injectio n of the CsA-DM-beta-CyD suspension into the sac was low er than that of th e CsA suspension alone. DM-beta-CyD inhibited the bioconversion of CsA in t he small intestinal microsomes of rats. These results indicate that the bio conversion of CsA was abated by complexation with DM-beta-CyD. An in vivo s tudy revealed that DM-beta-CyD increased the transfer of CsA to blood, not lymph, with low variability in the absorption after oral administration of the CsA suspension to rats. The variability of bioavailability of DM-beta-C yD complex was lower than that of Sandimmune, although the extent of bioava ilability of DM-beta-CyD was only a little higher than that of Sandimmune. The bioavailability of CsA or its DM-beta-CyD complex was appreciably decre ased by the cannulation of the bile duct of rats, and the extent of the low ering in the bioavailability in the presence of DM-beta-CyD was much less s erious than that of CsA alone. The present results suggest that DM-beta-CyD is particularly useful in designing oral preparations of CsA with an enhan ced bioavailability and a reduced variability in absorption.