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


CONCLUSIONS
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.
Department of Cardiovascular Pharmacology, AstraZeneca R&D Mölndal, S-431 83, Mölndal, Sweden. david.gustafsson@astrazeneca.com
D
D
Gustafsson
J
J
Nyström
S
S
Carlsson
U
U
Bredberg
U
U
Eriksson
E
E
Gyzander
M
M
Elg
T
T
Antonsson
K
K
Hoffmann
A
A
Ungell
H
H
Sörensen
S
S
Någård
A
A
Abrahamsson
R
R
Bylund
D000284:Administration, Oral; D000925:Anticoagulants / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001384:Azetidines / Q000008:administration & dosage / Q000493:pharmacokinetics; D001596:Benzylamines; D018938:Caco-2 Cells; D005998:Glycine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D006801:Humans; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics; D013917:Thrombin / Q000037:antagonists & inhibitors
D000925:Anticoagulants; D001384:Azetidines; D001596:Benzylamines; D011355:Prodrugs; C109573:melagatran; C426686:ximelagatran; D013917:Thrombin; D005998:Glycine