Enterohepatic disposition of rosuvastatin in pigs and the impact of concomitant dosing with cyclosporine and gemfibrozil
| Autor: | Lars Knutson, Mikael Hedeland, Ebba Bergman, Ulf Bondesson, Patrik Fridblom, Hans Lennernäs, Anna Lundahl |
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| Rok vydání: | 2009 |
| Předmět: |
Male
Swine Pharmaceutical Science Administration Oral Pharmacology Models Biological Intestinal absorption Pharmacokinetics Enterohepatic Circulation medicine Gemfibrozil Animals Bile Humans Rosuvastatin Rosuvastatin Calcium Infusions Intravenous Enterohepatic circulation Sulfonamides biology Chemistry nutritional and metabolic diseases Ciclosporin Hydroxymethylglutaryl-CoA reductase Fluorobenzenes Jejunum Pyrimidines Intestinal Absorption Liver Area Under Curve HMG-CoA reductase Injections Intravenous biology.protein Cyclosporine Microsomes Liver Female Hydroxymethylglutaryl-CoA Reductase Inhibitors Orchiectomy medicine.drug |
| Zdroj: | Drug metabolism and disposition: the biological fate of chemicals. 37(12) |
| ISSN: | 1521-009X |
| Popis: | 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 approximately 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. |
| Databáze: | OpenAIRE |
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