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Effect of a Single Gemfibrozil Dose on the Pharmacokinetics of Rosuvastatin in Bile and Plasma in Healthy Volunteers
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 Pharmacy. (Biopharmaceutics)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
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2010 (English)In: Journal of clinical pharmacology, ISSN 0091-2700, E-ISSN 1552-4604, Vol. 50, no 9, 1039-1049 p.Article in journal (Refereed) Published
Abstract [en]

The effect of a single intrajejunal dose of gemfibrozil (600 mg) on the plasma pharmacokinetics and biliary excretion of a single intrajejunal dose of rosuvastatin (20 mg) was investigated by using a multichannel catheter positioned in the distal duodenum/proximal jejunum in eight healthy volunteers. Bile and plasma samples were collected every 20 min for 200 min, with additional plasma samples being withdrawn for up to 48 hrs. Gemfibrozil did not affect the bioavailability of rosuvastatin, although it increased the apparent absorption phase during the initial 200 minutes (AUC0-200) by 1.56-fold (95%CI: 1.14-2.15). The interaction was less pronounced in this single dose study than in a previous report when gemfibrozil was administered repeatedly, nevertheless, the interaction coincided with the highest exposure to gemfibrozil. The plausible reason why the interaction in this investigation was only minor is the low exposure to gemfibrozil (and its metabolites), suggesting that the total plasma concentration of gemfibrozil needs to be above 20 µM in order to affect the disposition of rosuvastatin. This study demonstrates the value of monitoring the plasma pharmacokinetics of the inhibitor, and not only the drug under investigation, to improve the mechanistic interpretation.

Place, publisher, year, edition, pages
2010. Vol. 50, no 9, 1039-1049 p.
Keyword [en]
rosuvastatin, gemfibrozil, biliary excretion, pharmacokinetics, transport inhibition, drug-drug interactions
National Category
Pharmaceutical Sciences
Research subject
Biopharmaceutics
Identifiers
URN: urn:nbn:se:uu:diva-109827DOI: 10.1177/0091270009357432ISI: 000281858000006OAI: oai:DiVA.org:uu-109827DiVA: diva2:274079
Available from: 2009-10-26 Created: 2009-10-26 Last updated: 2017-12-12Bibliographically 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)
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Supervisors
Available from: 2009-11-13 Created: 2009-10-28 Last updated: 2009-11-13Bibliographically approved

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