The Metabolism and Disposition of the Oral Direct Thrombin Inhibitor, Dabigatran, in Humans
The pharmacokinetics and metabolism of the direct thrombin inhibitor dabigatran (BIBR 953 ZW, β-alanine, N -[[2-[[[4-(aminoiminomethyl)phenyl]amino]methyl]-1-methyl-1 H -benzimidazol-5-yl]carbonyl]- N -2-pyridinyl) were studied in 10 healthy males, who received 200 mg of [ 14 C]dabigatran etexilate...
Saved in:
Published in | Drug metabolism and disposition Vol. 36; no. 2; pp. 386 - 399 |
---|---|
Main Authors | , , , , |
Format | Journal Article |
Language | English |
Published |
Bethesda, MD
American Society for Pharmacology and Experimental Therapeutics
01.02.2008
|
Subjects | |
Online Access | Get full text |
Cover
Loading…
Summary: | The pharmacokinetics and metabolism of the direct thrombin inhibitor dabigatran (BIBR 953 ZW, β-alanine, N -[[2-[[[4-(aminoiminomethyl)phenyl]amino]methyl]-1-methyl-1 H -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 â¤0.6% of the dose in urine and 5.8% of the dose in feces following p.o. administration
and â¤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. |
---|---|
Bibliography: | ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-News-1 ObjectType-Feature-3 content type line 23 |
ISSN: | 0090-9556 1521-009X |
DOI: | 10.1124/dmd.107.019083 |