ABSTRACT: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 AUC bile /AUC VH 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 IC 50 values. However, cyclosporine significantly reduced the hepatic extraction of rosuvastatin (TI, 0.89 ؎ 0.06; TII, 0.46 ؎ 0.13) and increased the AUC VP and AUC VH by 1.6-and 9.1-fold, respectively. In addition, the biliary exposure and f e, bile were reduced by Ϸ50%. 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.Drug-drug interactions (DDIs) involving rosuvastatin that result in increased plasma exposure of rosuvastatin might, in rare cases, result in severe unwanted side effects such as myopathy and possibly rhabdomyolysis (Thompson et al., 2003). A 7.1-and 10.6-fold increase in the plasma exposure (AUC) and maximum plasma concentration (C max ) of a single 10-mg oral rosuvastatin dose was observed in heart transplant patients receiving cyclosporine treatment (75-200 mg b.i.d.) (Simonson et al., 2004). In addition, gemfibrozil (600 mg b.i.d.) increased the AUC and C max of a single 80-mg rosuvastatin dose by 1.88-and 2.21-fold, respectively .These clinically relevant DDIs are considered to involve inhibition of hepatic transport proteins although the in vivo relevant mechanism(s) remains to be elucidated. High hepatic exposure is essential for rosuvastatin, which exhibits its pharmacological effects by inhibiting HMG-Co A reductase, localized to the endoplasmic reticulum of the hepatocyte. Rosuvastatin has an estimated hepatic extraction of 0.63 in humans and the hepatic clearance accounts for approximately 70% of the total plasma clearance (Martin et al., 2003a). OATP1B1 (SLCO1B1) is reported to be the primary transporter involved; however, additional sinusoidal transporters...