RT Journal Article
SR Electronic
T1 Intestinal and Hepatobiliary Transport of Ximelagatran and Its Metabolites in Pigs
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1519
OP 1528
DO 10.1124/dmd.108.020412
VO 36
IS 8
A1 Elin Sjödin
A1 Holger Fritsch
A1 Ulf G. Eriksson
A1 Ulrika Logren
A1 Anders Nordgren
A1 Patrik Forsell
A1 Lars Knutson
A1 Hans Lennernäs
YR 2008
UL http://dmd.aspetjournals.org/content/36/8/1519.abstract
AB The direct thrombin inhibitor melagatran is formed from ximelagatran via two intermediate metabolites, OH-melagatran and ethylmelagatran. The biotransformation of ximelagatran does not involve cytochrome P450 isoenzymes, and it has been suggested that a reported interaction with erythromycin may instead be mediated by transport proteins. A pig model that simultaneously enables bile collection, sampling from three blood vessels and perfusion of a jejunal segment, was used to investigate the biotransformation of ximelagatran and the effect of erythromycin on the intestinal and hepatobiliary transport of ximelagatran and its metabolites. The pigs received enteral ximelagatran (n = 6), enteral ximelagatran together with erythromycin (n = 6), i.v. ximelagatran (n = 4), or i.v. melagatran (n = 4). The plasma exposure of the intermediates was found to depend on the route of ximelagatran administration. Erythromycin increased the area under the plasma concentration-time curve (AUC) of melagatran by 45% and reduced its biliary clearance from 3.0 ± 1.3 to 1.5 ± 1.1 ml/min/kg. Extensive biliary exposure of melagatran and ethylmelagatran, mediated by active transport, was evident from the 100- and 1000-fold greater AUC, respectively, in bile than in plasma. Intestinal efflux transporters seemed to be of minor importance for the disposition of ximelagatran and its metabolites considering the high estimated fabs of ximelagatran (80 ± 20%) and the negligible amount of the compounds excreted in the perfused intestinal segment. These findings suggest that transporters located at the sinusoidal and/or canalicular membranes of hepatocytes determine the hepatic disposition of ximelagatran and its metabolites, and are likely to mediate the ximelagatran-erythromycin pharmacokinetic interaction. The American Society for Pharmacology and Experimental Therapeutics