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Intestinal and Hepatobiliary Transport of Ximelagatran and Its Metabolites in Pigs

Department of Pharmacy, Uppsala University, Uppsala, Sweden (E.S., H.L.); Department of Surgical Sciences, University Hospital, Uppsala, Sweden (A.N., P.F., L.K.); and AstraZeneca R&D Mölndal, Mölndal, Sweden (H.F., U.E., U.L.)

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 f_abs 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.