Enterohepatic disposition of rosuvastatin in pigs and the impact of concomitant dosing with cyclosporine and gemfibrozil.
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.
Department of Pharmacy, Uppsala University,751 23 Uppsala, Sweden.
Ebba
E
Bergman
Anna
A
Lundahl
Patrik
P
Fridblom
Mikael
M
Hedeland
Ulf
U
Bondesson
Lars
L
Knutson
Hans
H
Lennernäs
D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001646:Bile / Q000378:metabolism*; D016572:Cyclosporine / Q000008:administration & dosage / Q000494:pharmacology*; D004764:Enterohepatic Circulation / Q000187:drug effects*; D005260:Female; D005464:Fluorobenzenes / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D015248:Gemfibrozil / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D007408:Intestinal Absorption / Q000187:drug effects; D007583:Jejunum / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D009919:Orchiectomy; D011743:Pyrimidines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D013552:Swine
D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; D016572:Cyclosporine; D000068718:Rosuvastatin Calcium; D015248:Gemfibrozil