Blech Stefan, Ebner Thomas, Ludwig-Schwellinger Eva, Stangier Joachim, Roth Willy
Boehringer Ingelheim Pharma GmbH & Co KG, Department of Drug Metabolism and Pharmacokinetics, Biberach, Germany.
Drug Metab Dispos. 2008 Feb;36(2):386-99. doi: 10.1124/dmd.107.019083. Epub 2007 Nov 15.
The pharmacokinetics and metabolism of the direct thrombin inhibitor dabigatran (BIBR 953 ZW, beta-alanine, N-[[2-[[[4-(aminoiminomethyl)phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]-N-2-pyridinyl) were studied in 10 healthy males, who received 200 mg of [(14)C]dabigatran etexilate (BIBR 1048 MS, the oral prodrug of dabigatran) or an i.v. infusion of 5 mg of [(14)C]dabigatran. Radioactivity was measured in plasma, urine, and feces over 1 week. The metabolite pattern was analyzed by high-performance liquid chromatography with on-line radioactivity detection, and metabolite structures were elucidated by mass spectrometry. Dabigatran etexilate was rapidly converted to dabigatran, with peak plasma dabigatran concentrations being attained after approximately 1.5 h; the bioavailability of dabigatran after p.o. administration of dabigatran etexilate was 7.2%. Dabigatran was predominantly excreted in the feces after p.o. treatment and in the urine after i.v. treatment. The mean terminal half-life of dabigatran was approximately 8 h. The predominant metabolic reaction was esterase-mediated hydrolysis of dabigatran etexilate to dabigatran. Phase I metabolites accounted for <or=0.6% of the dose in urine and 5.8% of the dose in feces following p.o. administration and <or=1.5 and 0.2%, respectively, following i.v. administration. Dabigatran acylglucuronides accounted for 0.4 and 4% of the dose in urine after p.o. and i.v. dosing, respectively. In vitro experiments confirmed that dabigatran etexilate is metabolized primarily by esterases and that cytochrome P450 plays no relevant role. These findings suggest that pharmacologically active concentrations of dabigatran are readily achieved after p.o. administration of dabigatran etexilate and that the potential for clinically relevant interactions between dabigatran and drugs metabolized by cytochrome P450 is low.
在10名健康男性中研究了直接凝血酶抑制剂达比加群（BIBR 953 ZW，β-丙氨酸，N-[[2-[[[4-(氨基亚氨甲基)苯基]氨基]甲基]-1-甲基-1H-苯并咪唑-5-基]羰基]-N-2-吡啶基）的药代动力学和代谢情况，这些受试者接受了200 mg的[(14)C]达比加群酯（BIBR 1048 MS，达比加群的口服前体药物）或静脉输注5 mg的[(14)C]达比加群。在1周内测定血浆、尿液和粪便中的放射性。通过带在线放射性检测的高效液相色谱分析代谢物模式，并通过质谱阐明代谢物结构。达比加群酯迅速转化为达比加群，血浆达比加群浓度在约1.5小时后达到峰值；口服达比加群酯后达比加群的生物利用度为7.2%。口服给药后达比加群主要经粪便排泄，静脉给药后经尿液排泄。达比加群的平均终末半衰期约为8小时。主要的代谢反应是酯酶介导的达比加群酯水解为达比加群。口服给药后，I相代谢物在尿液中占剂量的≤0.6%，在粪便中占剂量的5.8%；静脉给药后，分别占≤1.5%和0.2%。达比加群酰基葡萄糖醛酸在口服和静脉给药后在尿液中分别占剂量的0.4%和4%。体外实验证实达比加群酯主要由酯酶代谢，细胞色素P450不发挥相关作用。这些发现表明，口服达比加群酯后很容易达到具有药理活性浓度的达比加群，且达比加群与细胞色素P450代谢的药物之间发生临床相关相互作用的可能性较低。
