Hepatic disposition of ximelagatran and its metabolites in pig; prediction of the impact of membrane transporters through a simple disposition model
2010 (English)In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 27, no 4, 597-607 p.Article in journal (Refereed) Published
Purpose: The double prodrug ximelagatran is bioconverted, via the intermediates ethylmelagatran and N-hydroxymelagatran, to the direct thrombin inhibitor melagatran. The aims of this study were 1) to investigate the hepatic metabolism and disposition of ximelagatran and the intermediates in pig; and 2) to test a simple in vitro methodology for quantitative investigations of membrane transporters impact on the disposition of metabolized drugs. Methods: Porcine S1 (supernatant fraction obtained by centrifuging at 1000g for 10 min) liver fractions and hepatocytes were incubated in absence and presence of known membrane transporter inhibitors. The in vitro kinetics and disposition were determined by simultaneously fitting of the disappearance of ximelagatran and appearance of ethylmelagatran, N-hydroxymelagatran and melagatran. Results: In S1 liver fractions, the metabolism was significant inhibited by co-incubation of verapamil and ketoconazole but not by erythromycin, quinine and quinidine. The disposition of ximelagatran and the intermediate metabolites in hepatocytes were influenced, to various degrees, by carrier-mediated distribution processes. Conclusion: This work demonstrates that it is possible to obtain profound information of the general mechanisms important in the drug liver disposition with the combination of common in vitro systems and the simple disposition model proposed in this study.
Place, publisher, year, edition, pages
2010. Vol. 27, no 4, 597-607 p.
melagatran, prodrug, hepatic disposition, kinetic modeling, hepatocytes
Pharmacology and Toxicology
Research subject Drug Metabolism
IdentifiersURN: urn:nbn:se:uu:diva-110319DOI: 10.1007/s11095-009-0016-yISI: 000275556000007PubMedID: 20140637OAI: oai:DiVA.org:uu-110319DiVA: diva2:276139