There were no age-dependent differences in the absorption and biotransformation of ximelagatran, and the observed differences in exposure to melagatran can be explained by differences in renal function between the young and older subjects.

ABSTRACT: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.Ximelagatran was the first oral direct thrombin inhibitor to reach the market. As an oral anticoagulant, it had the potential to become an alternative to warfarin and other vitamin K antagonists; however, because of safety concerns involving hepatotoxicity, ximelagatran was withdrawn in 2006. Warfarin currently has an important role in the prevention and treatment of thromboembolic events but is unfortunately also associated with a variable pharmacokinetic and pharmacodynamic response, delayed onset and offset of action, numerous drug-drug interactions, and serious safety issues (Hawkins, 2004;Greenblatt and von Moltke, 2005). The narrow therapeutic index of warfarin and the many sources of variability require monitoring of the anticoagulant effect to maintain blood levels within the therapeutic range. Because of these difficulties and the severe consequences of thrombosis, it is clear that there is a need for new oral anticoagulants. Ximelagatran was developed to improve the low and highly variable bioavailability of the reversible, direct thrombin inhibitor melagatran (Gustafsson et al., 2001). The hydrophilic carboxylic acid and amidine functions of melagatran were protected by introducing an ethylester residue and the less ...

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