title: The effect of acute administration of rifampicin and imatinib on the enterohepatic transport of rosuvastatin in vivo.
abstract: Hepatobiliary transporters efficiently shunt rosuvastatin from the blood stream, into the hepatocyte, followed by transporter-mediated excretion into the bile ducts. This study aimed at investigating the contribution of sinusoidal versus canalicular transport on the pharmacokinetics of an intrajejunal dose of 80 mg rosuvastatin in pigs (control group, n = 2 + 6). The transport inhibitors, rifampicin (20 mg/kg, n = 6) and imatinib (14 mg/kg, n = 6), were administered as 2-h long intravenous infusions. Plasma samples were withdrawn from the portal and hepatic vein simultaneously during 5 h along with bile sample collection. Rifampicin reduced the hepatic extraction of rosuvastatin by 35% and the area under the curve in the hepatic vein compartment increased by a factor of 6.3 (95% confidence intervals (CI): 3.1-32, P value <0.01). The increase in the portal vein compartment was less pronounced than in the hepatic vein, 2.0-fold (95% CI: 1.1-3.8, P value <0.05), suggesting that the inhibition was predominantly located in the liver rather than in the intestine and suggesting inhibition if sinusoidal transport. In contrast, no effect on the pharmacokinetics of rosuvastatin was observed following concomitant administration with imatinib possibly due to insufficient concentration of the inhibitor inside the hepatocyte. Rifampicin significantly affected the hepatobiliary transport of rosuvastatin, however imatinib did not alter the plasma exposure of rosuvastatin.
authors.affiliation: Department of Pharmacy, Uppsala University, Uppsala, Sweden.
authors.forename: E
authors.initials: E
authors.lastname: Bergman
authors.forename: M
authors.initials: M
authors.lastname: Hedeland
authors.forename: U
authors.initials: U
authors.lastname: Bondesson
authors.forename: H
authors.initials: H
authors.lastname: Lennernäs
mesh_terms: D000284:Administration, Oral; D001549:Benzamides; D001646:Bile / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005464:Fluorobenzenes / Q000493:pharmacokinetics*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000493:pharmacokinetics*; D000068877:Imatinib Mesylate; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D010879:Piperazines / Q000008:administration & dosage*; D011743:Pyrimidines / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D012293:Rifampin / Q000008:administration & dosage*; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000493:pharmacokinetics*
chemical_list: D001549:Benzamides; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010879:Piperazines; D011743:Pyrimidines; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium; D000068877:Imatinib Mesylate; D012293:Rifampin