Hepatic disposition of ximelagatran and its metabolites in pig; prediction of the impact of membrane transporters through a simple disposition model.
OBJECTIVE
The double prodrug, ximelagatran, is bioconverted, via the intermediates ethylmelagatran and N-hydroxymelagatran, to the direct thrombin inhibitor, melagatran. The primary aim of this study was to investigate the hepatic metabolism and disposition of ximelagatran and the intermediates in pig. A secondary aim was to explore a simple in vitro methodology for quantitative investigations of the impact of membrane transporters on the disposition of metabolized drugs.


METHODS
Porcine S1 (supernatant fraction obtained by centrifuging at 1,000 g for 10 min) liver fractions and hepatocytes were incubated in the absence and presence of known membrane transporter inhibitors. The in vitro kinetics and disposition were determined by simultaneously fitting the disappearance of ximelagatran and the appearance of the metabolites.


RESULTS
In S1 liver fractions, the metabolism was significantly inhibited by co-incubation of verapamil or ketoconazole, but not by erythromycin, quinine or quinidine. The disposition of ximelagatran and the intermediate metabolites in hepatocytes were influenced, to various degrees, by carrier-mediated transport processes.


CONCLUSIONS
This work demonstrates that it is possible to obtain profound information on the general mechanisms that are important in the drug liver disposition using the combination of common in vitro systems and the simple disposition model proposed in this study.
Department of Pharmacy, Uppsala University, Box 580, 751 23, Uppsala, Sweden.
Erik
E
Sjögren
Ulf
U
Bredberg
Erik
E
Allard
Björn
B
Arvidsson
Jonas
J
Bergquist
Tommy B
TB
Andersson
Hans
H
Lennernäs
D000818:Animals; D000925:Anticoagulants / Q000378:metabolism*; D001384:Azetidines / Q000378:metabolism*; D001596:Benzylamines / Q000378:metabolism*; D003198:Computer Simulation; D022781:Hepatocytes / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D008954:Models, Biological; D011355:Prodrugs / Q000378:metabolism*; D013552:Swine
D000925:Anticoagulants; D001384:Azetidines; D001596:Benzylamines; D011355:Prodrugs; C426686:ximelagatran