uu.seUppsala University Publications
Change search
ReferencesLink to record
Permanent link

Direct link
Biliary secretion of rosuvastatin and bile acids in humans during the absorption phase.
Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
Faculty of Medicine, Department of Surgical Sciences. (Loc-I-Gut-gruppen)
Department of Medicinal Chemistry. (Analytisk Farmaceutisk Kemi)
Show others and affiliations
2006 (English)In: Eur J Pharm Sci, ISSN 0928-0987, Vol. 29, no 3-4, 205-14 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2006. Vol. 29, no 3-4, 205-14 p.
Keyword [en]
Adult, Bile/*metabolism, Bile Acids and Salts/*secretion, Female, Fluorobenzenes/*pharmacokinetics, Gallbladder/metabolism, Humans, Intestinal Absorption, Male, Pyrimidines/*pharmacokinetics, Sulfonamides/*pharmacokinetics
URN: urn:nbn:se:uu:diva-14707PubMedID: 16806856OAI: oai:DiVA.org:uu-14707DiVA: diva2:42478
Available from: 2008-06-25 Created: 2008-06-25 Last updated: 2011-01-11
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.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 115
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
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)
Available from: 2009-11-13 Created: 2009-10-28 Last updated: 2009-11-13Bibliographically approved

Open Access in DiVA

No full text

Other links


Search in DiVA

By author/editor
Bergman, EbbaForsell, PatrikTevell, AnnicaHedeland, MikaelBondesson, UlfKnutson, LarsLennernäs, Hans
By organisation
Department of PharmacyDepartment of Surgical SciencesDepartment of Medicinal Chemistry

Search outside of DiVA

GoogleGoogle Scholar

Altmetric score

Total: 173 hits
ReferencesLink to record
Permanent link

Direct link