Determination of melagatran, a novel, direct thrombin inhibitor, in human plasma and urine by liquid chromatography–mass spectrometry

Larsson, Margareta; Logren, Ulrika; Ahnoff, Martin; Lindmark, Bo; Abrahamsson, Peter; Svennberg, Henrik; Persson, Bengt‐Arne

doi:10.1016/s0378-4347(01)00429-7

Cited by 50 publications

(24 citation statements)

References 5 publications

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“…Plasma from dogs was analyzed with an LOQ of 0.025 M for ximelagatran, ethyl-melagatran, and melagatran, and 0.050 M for OHmelagatran. Urine from the human ximelagatran study was also analyzed using LC-MS with an LOQ for all compounds of 0.10 M. These analytical methods for determination of melagatran only (Larsson et al, 2002) and for determination of all four analytes (Larsson et al, 2003) in biological fluids, with several enhancements, have recently been published. A bi-exponential model was fit to the data obtained after i.v.…”

Section: Sample Analysismentioning

confidence: 99%

Absorption, Distribution, Metabolism, and Excretion of Ximelagatran, an Oral Direct Thrombin Inhibitor, in Rats, Dogs, and Humans

Eriksson¹,

Bredberg²,

Hoffmann³

et al. 2003

Drug Metab Dispos

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154

167

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ABSTRACT:The absorption, metabolism, and excretion of the oral direct thrombin inhibitor, ximelagatran, and its active form, melagatran, were separately investigated in rats, dogs, and healthy male human subjects after administration of oral and intravenous (i.v.) single doses. Ximelagatran was rapidly absorbed and metabolized following oral administration, with melagatran as the predominant compound in plasma. Two intermediates (ethyl-melagatran and OH-melagatran) that were subsequently metabolized to melagatran were also identified in plasma and were rapidly eliminated. Melagatran given i.v. had relatively low plasma clearance, small volume of distribution, and short elimination half-life. The oral absorption of melagatran was low and highly variable. It was primarily renally cleared, and the renal clearance agreed well with the glomerular filtration rate. Ximelagatran was extensively metabolized, and only trace amounts were renally excreted. Melagatran was the major compound in urine and feces after administration of ximelagatran. Appreciable quantities of ethyl-melagatran were also recovered in rat, dog, and human feces after oral administration, suggesting reduction of the hydroxyamidine group of ximelagatran in the gastrointestinal tract, as demonstrated when ximelagatran was incubated with feces homogenate. Polar metabolites in urine and feces (all species) accounted for a relatively small fraction of the dose. The bioavailability of melagatran following oral administration of ximelagatran was 5 to 10% in rats, 10 to 50% in dogs, and about 20% in humans, with low between-subject variation. The fraction of ximelagatran absorbed was at least 40 to 70% in all species. First-pass metabolism of ximelagatran with subsequent biliary excretion of the formed metabolites account for the lower bioavailability of melagatran.

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Section: Sample Analysismentioning

confidence: 99%

Absorption, Distribution, Metabolism, and Excretion of Ximelagatran, an Oral Direct Thrombin Inhibitor, in Rats, Dogs, and Humans

Eriksson¹,

Bredberg²,

Hoffmann³

et al. 2003

Drug Metab Dispos

Self Cite

154

167

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“…Melagatran plasma concentrations were determined by a liquid chromatographic-mass spectrometric method [14]. The relative standard deviation of the assay at melagatran concentrations of 10 and 25 nmol/l was 1-5%.…”

Section: Plasma Melagatran Concentrationsmentioning

confidence: 99%

Vitamin K deficiency amplifies anticoagulation response to ximelagatran: possible implications for direct thrombin inhibitors and their clinical safety

2008

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“…Plasma concentrations of melagatran were measured using liquid chromatography-mass spectrometry [19]. The limit of quantification was 0.010 Ìmol/l.…”

Section: Analysesmentioning

confidence: 99%

Effects of the Oral Direct Thrombin Inhibitor Ximelagatran on P-Selectin Expression and Thrombin Generation in Atrial Fibrillation

Wolzt

Boström²,

Svensson³

et al. 2003

Pathophysiol Haemos Thromb

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This study investigated the pharmacodynamic effects of the oral direct thrombin inhibitor ximelagatran on platelet activation and thrombin generation in patients with nonvalvular atrial fibrillation. Using an open, group-matched study design, the effects of ximelagatran (36 mg twice daily for 5 days) were studied in 12 patients with permanent nonvalvular atrial fibrillation and in 12 healthy controls. After ximelagatran for 5 days, elevated platelet P-selectin expression in atrial fibrillation patients was lowered to that during coumarin treatment or in controls but had no effect in control subjects. Using the endogenous thrombin potential as a marker, ximelagatran decreased and delayed thrombin generation in both groups. In conclusion, direct thrombin inhibition with ximelagatran reduced elevated platelet P-selectin expression and inhibited thrombin generation.

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Determination of melagatran, a novel, direct thrombin inhibitor, in human plasma and urine by liquid chromatography–mass spectrometry

Cited by 50 publications

References 5 publications

Absorption, Distribution, Metabolism, and Excretion of Ximelagatran, an Oral Direct Thrombin Inhibitor, in Rats, Dogs, and Humans

Absorption, Distribution, Metabolism, and Excretion of Ximelagatran, an Oral Direct Thrombin Inhibitor, in Rats, Dogs, and Humans

Vitamin K deficiency amplifies anticoagulation response to ximelagatran: possible implications for direct thrombin inhibitors and their clinical safety

Effects of the Oral Direct Thrombin Inhibitor Ximelagatran on P-Selectin Expression and Thrombin Generation in Atrial Fibrillation

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