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The Effect of Acute Administration of Rifampicin and Imatinib on the Enterohepatic Transport of Rosuvastatin In Vivo
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. (Biopharmaceutics)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. (Biopharmaceutics)
2010 (English)In: Xenobiotica, ISSN 0049-8254, E-ISSN 1366-5928, Vol. 40, no 8, 558-568 p.Article in journal (Refereed) Published
Abstract [en]

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 80mg rosuvastatin in pigs (control group, n=2+6). The transport inhibitors, rifampicin (20mg/kg, n6) and imatinib (14mg/kg, n6), were administered as 2-h long intravenous infusions. Plasma samples were withdrawn from the portal and hepatic vein simultaneously during 5h along with bile sample collection.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): 3.132, P value <0.01). The increase in the portal vein compartment was less pronounced than in the hepatic vein, 2.0-fold (95% CI: 1.13.8, 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.

Place, publisher, year, edition, pages
2010. Vol. 40, no 8, 558-568 p.
Keyword [en]
Biliary excretion, Hepatobiliary transport, rifampicin, imatinib, inhibition, pharmacokinetics
National Category
Pharmaceutical Sciences
Research subject
Biopharmaceutics
Identifiers
URN: urn:nbn:se:uu:diva-109826DOI: 10.3109/00498254.2010.496498ISI: 000280993200004OAI: oai:DiVA.org:uu-109826DiVA: diva2:274078
Available from: 2009-10-26 Created: 2009-10-26 Last updated: 2011-10-13Bibliographically approved
In thesis
1. The Hepatobiliary Transport of Rosuvastatin In Vivo
Open this publication in new window or tab >>The Hepatobiliary Transport of Rosuvastatin In Vivo
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In vivo studies of hepatobiliary disposition are challenging. The hepatobiliary system is complex, as its physiological localization, complex cellular structure with numerous transporters and enzymes, and the interindividual variability in protein expression and biliary flow will all affect the in vivo disposition of a drug under investigation. The research included in this thesis has focused on the involvement of hepatic transport proteins in the hepatobiliary disposition of rosuvastatin. The impact that several transport inhibitors had on the pharmacokinetics of rosuvastatin was investigated in healthy volunteers and in pigs. The effects were considerable, following inhibition of sinusoidal transport proteins by cyclosporine and rifampicin. These inhibitors significantly reduced the hepatic extraction of rosuvastatin by 50 and 35%, respectively, and the plasma exposure increased by factors of 9.1 and 6.3, respectively. Drug-drug interactions (DDI) resulting in markedly higher plasma exposures are important from a drug safety perspective as increased extrahepatic exposure of statins is associated with an increased risk of severe side-effects, such as myopathy which in rare cases could develop into rhabdomyolysis. The DDI caused by cyclosporine and rifampicin can probably be attributed to inhibition of hepatic uptake transporters. In contrast, inhibition of canalicular transporters by imatinib did not significantly affect the pharmacokinetics of rosuvastatin, which suggests that the intracellular concentration of the inhibitor in the hepatocyte was insufficient to affect the transport of rosuvastatin, or that imatinib is not a sufficiently potent inhibitor in vivo. Furthermore, gemfibrozil administered as a single dose into the jejunum in healthy volunteers and pigs did not affect the plasma or biliary pharmacokinetics of rosuvastatin. The previously reported DDI in humans upon repeated dosing with gemfibrozil might be explained by the accumulation of metabolites able to affect the disposition of rosuvastatin. The investigations presented in this thesis conclude that transport proteins are of considerable importance for the hepatobiliary disposition of rosuvastatin in vivo. The Loc-I-Gut catheter can be applied for the investigation of biliary accumulation and to determine bile specific metabolites, however it has limitations when conducting quantitative measurements. In the porcine model, hepatic bile can be collected for up to six hours and enables the determination of the hepatic extraction in vivo.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 59 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 115
Keyword
Rosuvastatin, Biliary excretion, Transport inhibition, Pharmacokinetics, Drug-drug interactions, Hepatobiliary transport, Organic anion transporting polypeptide, OATP, Statins, Gemfibrozil, Cyclosporine, Imatinib, Rifampicin, Canalicular transport, Sinusoidal transport, Hepatic uptake, Hepatic extraction
National Category
Pharmaceutical Sciences
Research subject
Biopharmaceutics
Identifiers
urn:nbn:se:uu:diva-109866 (URN)978-91-554-7648-9 (ISBN)
Public defence
2009-12-04, Biomedicinskt centrum, B21, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2009-11-13 Created: 2009-10-28 Last updated: 2009-11-13Bibliographically approved

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