Sjödin Elin, Fritsch Holger, Eriksson Ulf G, Logren Ulrika, Nordgren Anders, Forsell Patrik, Knutson Lars, Lennernäs Hans
Department of Pharmacy, Uppsala University, Box 580, SE-751 23 Uppsala, Sweden.
Drug Metab Dispos. 2008 Aug;36(8):1519-28. doi: 10.1124/dmd.108.020412. Epub 2008 May 5.
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.
直接凝血酶抑制剂美拉加群是由希美加群经两种中间代谢产物OH - 美拉加群和乙基美拉加群形成的。希美加群的生物转化不涉及细胞色素P450同工酶，有研究表明，报道的其与红霉素的相互作用可能是由转运蛋白介导的。采用一种能同时收集胆汁、从三根血管取样并对空肠段进行灌注的猪模型，来研究希美加群的生物转化以及红霉素对希美加群及其代谢产物在肠道和肝胆转运的影响。猪分别接受肠内给予希美加群（n = 6）、肠内给予希美加群并同时给予红霉素（n = 6）、静脉注射希美加群（n = 4）或静脉注射美拉加群（n = 4）。发现中间代谢产物的血浆暴露量取决于希美加群的给药途径。红霉素使美拉加群的血浆浓度 - 时间曲线下面积（AUC）增加了45%，并使其胆汁清除率从3.0±1.3降至1.5±1.1 ml/min/kg。美拉加群和乙基美拉加群在胆汁中的大量暴露是由主动转运介导的，胆汁中的AUC分别比血浆中的大100倍和1000倍，这一点很明显。考虑到希美加群的高估计吸收分数（80±20%）以及灌注肠段中排泄的化合物量可忽略不计，肠道外排转运体似乎对希美加群及其代谢产物的处置不太重要。这些发现表明，位于肝细胞窦状隙和/或胆小管膜上的转运体决定了希美加群及其代谢产物的肝脏处置，并且可能介导了希美加群 - 红霉素的药代动力学相互作用。
