The effect of acute administration of rifampicin and imatinib on the enterohepatic transport of rosuvastatin in vivo

Abstract

1. Hepatobiliary transporters efficiently shunt rosuvastatin from the blood stream, into the hepatocyte, followed by transporter-mediated excretion into the bile ducts.

2. 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 Plasma samples were withdrawn from the portal and hepatic vein simultaneously during 5 h along with bile sample collection.

3. 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.

4. Rifampicin significantly affected the hepatobiliary transport of rosuvastatin, however imatinib did not alter the plasma exposure of rosuvastatin.

Keywords::

• Drug transport
• OATP1B1
• biliary excretion
• inhibition of drug transport
• pharmacokinetics
• porcine
• BCRP

Acknowledgement

We would like to express our gratitude to RN Anders Nordgren for his excellent technical assistance.

Declaration of interest

Dr. Bergman, Dr. Hedeland, and Dr. Bondesson report no declarations of interest. Dr. Lennernäs reports receiving grant support from AstraZeneca.