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 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.
Footnotes
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.109.029363
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- DDI
- drug-drug interaction
- AUC
- area under the concentration-time curve
- OATP
- organic anion-transporting polypeptide
- NTCP
- human sodium-dependent taurocholate cotransporting polypeptide
- BCRP
- breast cancer resistance protein
- MRP2
- multidrug resistance-associated protein 2
- VH
- hepatic vein
- VP
- portal, vein
- VF
- femoral vein
- HLM
- human liver microsome
- PLM
- pig liver microsome
- LC-MS/MS
- liquid chromatography-tandem mass spectrometry
- HPLC
- high-performance liquid chromatography
- ESI
- electrospray ionization
- RSD
- relative standard deviation
- CI
- confidence interval
- i.j.
- intrajejunal.
- Received July 7, 2009.
- Accepted September 15, 2009.
- Copyright © 2009 by The American Society for Pharmacology and Experimental Therapeutics
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