PT - JOURNAL ARTICLE AU - Ebba Bergman AU - Anna Lundahl AU - Patrik Fridblom AU - Mikael Hedeland AU - Ulf Bondesson AU - Lars Knutson AU - Hans Lennernäs TI - Enterohepatic Disposition of Rosuvastatin in Pigs and the Impact of Concomitant Dosing with Cyclosporine and Gemfibrozil AID - 10.1124/dmd.109.029363 DP - 2009 Dec 01 TA - Drug Metabolism and Disposition PG - 2349--2358 VI - 37 IP - 12 4099 - http://dmd.aspetjournals.org/content/37/12/2349.short 4100 - http://dmd.aspetjournals.org/content/37/12/2349.full SO - Drug Metab Dispos2009 Dec 01; 37 AB - The hepatobiliary transport and local disposition of rosuvastatin in pig were investigated, along with the impact of concomitant dosing with two known multiple transport inhibitors; cyclosporine and gemfibrozil. Rosuvastatin (80 mg) was administered as an intrajejunal bolus dose in treatments I, II, and III (TI, TII, and TIII, respectively; n = 6 per treatment). Cyclosporine (300 mg) and gemfibrozil (600 mg) were administered in addition to the rosuvastatin dose in TII and TIII, respectively. Cyclosporine was administered as a 2-h intravenous infusion and gemfibrozil as an intrajejunal bolus dose. In treatment IV (TIV, n = 4) 5.9 mg of rosuvastatin was administered as an intravenous bolus dose. The study was conducted using a pig model, which enabled plasma sampling from the portal (VP), hepatic (VH), and femoral veins and bile from the common hepatic duct. The biliary recoveries of the administered rosuvastatin dose were 9.0 ± 3.5 and 35.7 ± 15.6% in TI and TIV, respectively. Rosuvastatin was highly transported into bile as shown by the median AUCbile/AUCVH ratio in TI of 1770 (1640–11,300). Gemfibrozil did not have an effect on the plasma pharmacokinetics of rosuvastatin, most likely because the unbound inhibitor concentrations did not exceed the reported IC50 values. However, cyclosporine significantly reduced the hepatic extraction of rosuvastatin (TI, 0.89 ± 0.06; TII, 0.46 ± 0.13) and increased the AUCVP and AUCVH by 1.6- and 9.1-fold, respectively. In addition, the biliary exposure and fe, bile were reduced by ≈50%. The strong effect of cyclosporine was in accordance with inhibition of sinusoidal uptake transporters, such as members of the organic anion-transporting polypeptide family, rather than canalicular transporters.Copyright © 2009 by The American Society for Pharmacology and Experimental Therapeutics