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Extensive intestinal glucuronidation of raloxifene in vivo in pigs and impact for oral drug delivery
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. (The Biopharmaceutic group)
AstraZeneca R&D Alderley Park, Macclesfield, UK.
AstraZeneca R&D Alderley Park, Macclesfield, UK.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. (The Biopharmaceutic group)
2012 (English)In: Xenobiotica, ISSN 0049-8254, E-ISSN 1366-5928, Vol. 42, no 9, 917-928 p.Article in journal (Refereed) Published
Abstract [en]

1. In this study an advanced multisampling site pig model, with simultaneous venous blood sampling pre- and post liver, was applied to quantify the role of the intestine in relation to the liver in first-pass glucuronidation of raloxifene in vivo. The pharmacokinetic of raloxifene (a BCS/BDDCS class II compound) in humans is characterized by extensive metabolism (>90%) and the major metabolite is the 4'-beta-glucuronide (R-4-G).

2. Following intra-jejunal (i.j.) single dose administration in pigs raloxifene was metabolized in the gut (E G) during first-pass to more than 70% and a high concentration (AUC(0-6 h) ratio R-4-G/raloxifene >100) of R-4-G was reached in the portal vein. The hepatic extraction (E-H) of raloxifene was similar to 50% and as in humans the bioavailability become low (similar to 7%) in pigs. Interestingly the E-H of raloxifene and R-4-G was time-dependent after i.j. administration.

3. It is clear that the gut was the dominating organ in first-pass extraction of raloxifene in vivo in pigs. The quantification in this study support earlier human data and emphasize that intestinal glucuronidation should be considered early in the pharmaceutical development.

Place, publisher, year, edition, pages
2012. Vol. 42, no 9, 917-928 p.
Keyword [en]
Raloxifene, glucuronidation, pigs, intestinal metabolism, first-pass metabolism
National Category
Pharmaceutical Sciences
Research subject
Biopharmaceutics
Identifiers
URN: urn:nbn:se:uu:diva-165511DOI: 10.3109/00498254.2012.683497ISI: 000307301900011OAI: oai:DiVA.org:uu-165511DiVA: diva2:474021
Available from: 2012-01-09 Created: 2012-01-09 Last updated: 2017-12-08Bibliographically approved
In thesis
1. First-pass Intestinal Metabolism of Drugs: Experiences from in vitro, in vivo and simulation studies
Open this publication in new window or tab >>First-pass Intestinal Metabolism of Drugs: Experiences from in vitro, in vivo and simulation studies
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The bioavailability of a drug can be described as the fraction of an orally administered dose that reaches the systemic circulation and is often limited by first-pass metabolism in the gut and the liver. It is important to have knowledge about these processes since the systemic blood drug concentration is tightly connected to the effect of the drug.

The general aim of this project was to quantitatively examine the role of the intestine in relation to the liver in first-pass metabolism of orally administered drugs. The first-pass metabolism of verapamil and raloxifene was investigated in detail with in vivo, in vitro and simulation studies, using the pig as an experimental model.

The intestine contributed to the same extent as the liver to first-pass metabolism of R/S-verapamil in vivo in pigs. The S-isomer of verapamil was found in lower plasma concentrations compared to the R-isomer after oral dosing. The in vitro metabolism of verapamil in pig and human liver showed interspecies similarity and indicated equal intrinsic clearance for R- and S-verapamil. Through physiologically based pharmacokinetic modeling the stereoselectivity was explained by a combination of several processes, including enantioselective plasma protein binding, blood-to-plasma partition, and gut and liver tissue distribution. For raloxifene the intestine was the dominating organ in first-pass glucuronidation in vivo in pigs. Furthermore, the raloxifene concentration entering the intestine or the dose administered in the gut did not influence the plasma PK of raloxifene and indicated that the intestinal metabolism was not saturable with clinical relevant doses. For both verapamil and raloxifene, a time-dependent hepatic metabolism was noted with major consequences to the pharmacokinetic of the drugs.

This project has pointed out the importance of intestinal metabolism in the overall first-pass extraction of drugs and indicates that intestinal metabolism should be considered and evaluated early in drug development.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 66 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 153
Keyword
pharmacokinetics, metabolism, CYP3A4, CYP2C9, CYP2D6, UGT, glucuronidation, physiologically based pharmacokinetic model, modelling
National Category
Pharmaceutical Sciences
Research subject
Biopharmaceutics
Identifiers
urn:nbn:se:uu:diva-165514 (URN)978-91-554-8251-0 (ISBN)
Public defence
2012-02-24, B42, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2012-02-03 Created: 2012-01-09 Last updated: 2012-02-15Bibliographically approved

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Thörn, Helena AnnaLennernäs, Hans

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