The direct thrombin inhibitor melagatran and its oral prodrug H 376/95: intestinal absorption properties, biochemical and pharmacodynamic effects

Thromb Res. 2001 Feb 1;101(3):171-81. doi: 10.1016/s0049-3848(00)00399-6.


Suboptimal gastrointestinal absorption is a problem for many direct thrombin inhibitors. The studies presented herein describe the new oral direct thrombin inhibitor H 376/95, a prodrug with two protecting residues added to the direct thrombin inhibitor melagatran. Absorption properties in vitro: H 376/95 is uncharged at intestinal pH while melagatran is charged. H 376/95 is 170 times more lipophilic (octanol water partition coefficient) than melagatran. As a result, the permeability coefficient across cultured epithelial Caco-2 cells is 80 times higher for H 376/95 than for melagtran. Pharmacokinetic studies in healthy volunteers: H 376/95 is converted to melagatran in man. Oral bioavailability, measured as melagatran in plasma, is about 20% after oral administration of H 376/95, which is 2.7-5.5 times higher than after oral administration of melagatran. The variability in the area under the drug plasma concentration vs. time curve (AUC) is much smaller with oral H 376/95 (coefficient of variation 20%) than with oral melagatran (coefficient of variation 38%). Pharmacodynamic properties: H 376/95 is inactive towards human alpha-thrombin compared with melagatran [inhibition constant (K(i)) ratio, 185 times], a potential advantage for patients with silent gastrointestinal bleeding. In an experimental thrombosis model in the rat, oral H 376/95 was more effective than the subcutaneous low molecular weight heparin dalteparin in preventing thrombosis.

Conclusion: By the use of the prodrug principle, H 376/95 endows the direct thrombin inhibitor melagatran with pharmacokinetic properties required for oral administration without compromising the promising pharmacodynamic properties of melagatran.

MeSH terms

  • Administration, Oral
  • Anticoagulants / administration & dosage
  • Anticoagulants / pharmacokinetics*
  • Azetidines / administration & dosage
  • Azetidines / pharmacokinetics
  • Benzylamines
  • Caco-2 Cells
  • Glycine / administration & dosage
  • Glycine / analogs & derivatives
  • Glycine / pharmacokinetics*
  • Humans
  • Intestinal Absorption
  • Intestinal Mucosa / drug effects*
  • Intestinal Mucosa / metabolism
  • Male
  • Prodrugs / administration & dosage
  • Prodrugs / pharmacokinetics
  • Thrombin / antagonists & inhibitors


  • Anticoagulants
  • Azetidines
  • Benzylamines
  • Prodrugs
  • melagatran
  • ximelagatran
  • Thrombin
  • Glycine