Studies On Relationship Between Inhibition Of P-glycoprotein Drug Pump By Excipients And Intestinal Absorption Of Cyclosporine A

Intestinal P-glycoprotein (P-gp), which is expressed at the apical membranes of the epithelial cells in intestine, can pump the drugs that have been absorbed back into the intestinal lumen, and thus reduce the absorption of a wide range of drugs that are orally administered. Cyclosporine A (CsA) is a potent immunosuppressive agent, which is widely used to prevent rejection in organ transplants and to treat autoimmune diseases by oral administration. In recent years, intestinal P-gp has been considered as an important factor that contributes to the poor intestinal absorption of CsA (P-gp substrate). Thus excipient inhibitors can theoretically improve the poor oral bioavailability of CsA by inhibition of intestinal P-gp.We employed the everted rat gut sac system as an in vitro model in order to demonstrate the effects of four pharmaceutical excipients (EL-35, F-68, T-80 and PEG-400) on intestinal absorption of CsA without influences of nerves and blood flows. The results showed that 250μg·ml^-1 verapamil hydrochloride (68.31%), 1mg·ml^-1 EL-35 (30.82%), 10mg·ml^-1 F-68 (29.41%), 1mg·ml^-1 T-80 (27.23%), 5mg·ml^-1 PEG-400 (23.16%) and 10mg·ml^-1 PEG-400 (42.08%) could significantly enhance the absorption amount of CsA at 90 min in everted gut sac system.Animal model was carried out to investigate the possible effect of EL-35, F-68, T-80 and PEG-400 on the pharmacokinetics of cyclosporine A by oral gavage administration in rats. The results showed that maximum blood drug concentration (Cmax) was increased significantly by 10mg·kg^-1 verapamil hydrochloride (227.99%), 100mg·kg^-1 EL-35 (83.76%), 200mg·kg^-1 EL-35 (141.15%), 200mg·kg^-1 F-68 (52.02%), 100mg·kg^-1 T-80 (59.64%), 200mg·kg^-1 T-80 (60.29%), 20mg·kg^-1 PEG-400 (30.01%), 100mg·kg^-1 PEG-400 (78.00%) and 200mg·kg^-1 PEG-400 (143.29%), and area under the time-concentration curve (AUC0-t) was enhanced significantly by 10mg·kg^-1 verapamil hydrochloride (285.95%), 100mg·kg^-1 EL-35 (89.39%), 200mg·kg^-1 EL-35 (148.37%), 100mg·kg^-1 F-68 (39.01%), 200mg·kg^-1 F-68 (50.07), 200mg·kg^-1 T-80 (85.68%), 20mg·kg^-1 PEG-400 (42.45%), 100mg·kg^-1 PEG-400 (79.03%) and 200mg·kg^-1 PEG-400 (92.44%).In conclusion, EL-35, F-68, T-80 and PEG-400 can enhance the intestinal absorption and thus improve oral bioavailability of CsA as a result of P-gp inhibition. The results of present studies provided a new idea and a useful method for improving poor bioavailability of CsA, and established theoretical basis for developing new CsA drug delivery system by inhibition of P-gp.