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

Direct link
Effects of ketoconazole on the in vivo biotransformation and hepatobiliary transport of the thrombin inhibitor AZD0837 in pigs
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
Show others and affiliations
2011 (English)In: Drug Metabolism And Disposition, ISSN 0090-9556, E-ISSN 1521-009X, Vol. 39, no 2, 239-246 p.Article in journal (Refereed) Published
Abstract [en]

Ketoconazole has been shown in clinical trials to increase the plasma exposure of the oral anticoagulant prodrug AZD0837 [(2S)-N-{4- [(Z)-amino(methoxyimino)methyl]benzyl}-1-{(2R)-2-[3-chloro-5-(difluoromethoxy)phenyl]-2-hydroxyethanoyl}-azetidine-2-carboxamide] and its active metabolite, AR-H067637 [(2S)-N-{4-[amino(imino)methyl]benzyl}-1-{(2R)-2-[3-chloro-5-(difluoromethoxy)phenyl]-2-hydroxyethanoyl}-azetidine-2-carboxamide]. To investigate the biotransformation of AZD0837 and the effect of ketoconazole on this process, we used an experimental model in pigs that allows repeated sampling from three blood vessels, the bile duct, and a perfused intestinal segment. The pigs received AZD0837 (500 mg) given enterally either alone (n = 5) or together with single-dose ketoconazole (600 mg) (n = 6). The prodrug (n = 2) and its active metabolite (n = 2) were also administered intravenously to provide reference doses. The plasma data revealed considerable interindividual variation in the exposure of the prodrug, intermediate metabolite, and active metabolite. However, AR-H067637 was detected at very high concentrations in the bile with low variability (Ae(bile) = 53 ± 6% of the enteral dose), showing that the compound had indeed been formed in all of the animals and efficiently transported into the bile canaliculi. Concomitant dosing with ketoconazole increased the area under the plasma concentration-time curve for AZD0837 (by 99%) and for AR-H067637 (by 51%). The effect on the prodrug most likely arose from inhibited CYP3A-mediated metabolism. Reduced metabolism also seemed to explain the increased plasma exposure of the active compound because ketoconazole prolonged the terminal half-life with no apparent effect on the extensive biliary excretion and biliary clearance. These in vivo results were supported by in vitro depletion experiments for AR-H067637 in pig liver microsomes with and without the addition of ketoconazole.

Place, publisher, year, edition, pages
2011. Vol. 39, no 2, 239-246 p.
Keyword [en]
hepatobiliary transport, biliary clearance, drug-drug interaction, AZD0837, ketoconazole, direct thrombin inhibitors
National Category
Pharmaceutical Sciences
URN: urn:nbn:se:uu:diva-123417DOI: 10.1124/dmd.110.035022ISI: 000286317900011PubMedID: 20978106OAI: oai:DiVA.org:uu-123417DiVA: diva2:313925
Available from: 2010-04-27 Created: 2010-04-27 Last updated: 2011-02-15Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full textPubMed

Search in DiVA

By author/editor
Matsson, Elin
By organisation
Department of PharmacyDepartment of Surgical Sciences
In the same journal
Drug Metabolism And Disposition
Pharmaceutical Sciences

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 173 hits
ReferencesLink to record
Permanent link

Direct link