Department of Pharmacy, Uppsala University, Box 580, 751 23, Uppsala, Sweden.
Pharm Res. 2010 Apr;27(4):597-607. doi: 10.1007/s11095-009-0016-y. Epub 2010 Feb 6.
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.
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.
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.
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.
双前药西米拉坦经中间体乙基米拉坦和 N-羟甲基拉坦生物转化为直接凝血酶抑制剂米拉坦。本研究的主要目的是研究猪体内西米拉坦及其中间体的肝代谢和处置。次要目的是探索一种简单的体外方法学，用于定量研究膜转运体对代谢药物处置的影响。
在不存在和存在已知膜转运体抑制剂的情况下，孵育猪 S1（通过在 1000g 下离心 10 分钟获得的上清液级分）肝级分和肝细胞。通过同时拟合西米拉坦的消失和代谢物的出现来确定体外动力学和处置。
在 S1 肝级分中，维拉帕米或酮康唑的共孵育显著抑制了代谢，但红霉素、奎宁或奎尼丁则没有。西米拉坦和中间代谢物在肝细胞中的处置受到载体介导的转运过程的不同程度影响。
这项工作表明，使用常见的体外系统和本研究中提出的简单处置模型的组合，有可能获得关于在药物肝脏处置中起重要作用的一般机制的深刻信息。
