The Enterohepatic Disposition of Rosuvastatin in Pigs and The Impact of Concomitant Dosing with Cyclosporine and Gemfibrozil
2009 (English)In: Drug Metabolism And Disposition, ISSN 0090-9556, E-ISSN 1521-009X, Vol. 37, no 12, 2349-2358 p.Article in journal (Refereed) Published
The hepatobiliary transport and local disposition of rosuvastatin in pig was investigated, along with the impact of concomitant dosing with two known multiple transport inhibitors; cyclosporine and gemfibrozil. 80 mg rosuvastatin 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 two hour intravenous infusion and gemfibrozil as an intrajejunal bolus dose. In Treatment IV (TIV, n=4) was 5.9 mg rosuvastatin 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 recovery of the administered rosuvastatin dose was 9.0±3.5% and 35.7±15.6% in TI and TIV, respectively. Rosuvastatin was highly transported into bile as the median AUCbile/AUCVH ratio was 1770 (1640-11300) in TI. 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 OATP-family, rather than canalicular transporters.
Place, publisher, year, edition, pages
2009. Vol. 37, no 12, 2349-2358 p.
rosuvastatin, cyclosporine, gemfibrozil, transport inhibition, biliary excretion, hepatobiliary transport, pharmacokinetics
Research subject Biopharmaceutics
IdentifiersURN: urn:nbn:se:uu:diva-109828DOI: 10.1124/dmd.109.029363ISI: 000271935200011OAI: oai:DiVA.org:uu-109828DiVA: diva2:274080