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

UNLABELLED 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.

[1]  B. Eriksson,et al.  Antithrombotic Effect of Two Low Molecular Weight Thrombin Inhibitors and a Low-Molecular Weight Heparin in a Caval Vein Thrombosis Model in the Rat , 1997, Thrombosis and Haemostasis.

[2]  R. Peto,et al.  Haemodilution in acute stroke: Results of the Italian haemodilution trial , 1988 .

[3]  J. Mehta,et al.  Melagatran, an oral active-site inhibitor of thrombin, prevents or delays formation of electrically induced occlusive thrombus in the canine coronary artery. , 1998, Journal of cardiovascular pharmacology.

[4]  Sangsoo Kim,et al.  Benzylamine-based selective and orally bioavailable inhibitors of thrombin. , 1998, Bioorganic & medicinal chemistry letters.

[5]  J. Stürzebecher,et al.  Synthetic inhibitors of thrombin and factor Xa: from bench to bedside. , 1999, Thrombosis research.

[6]  P E Sanderson,et al.  Small, noncovalent serine protease inhibitors , 1999, Medicinal research reviews.

[7]  I. Mackie,et al.  Pharmacokinetics and pharmacodynamics of Ro 44-3888 after single ascending oral doses of sibrafiban, an oral platelet aggregation inhibitor, in healthy male volunteers. , 1999, British journal of clinical pharmacology.

[8]  N. W. Barker,et al.  A PREPARATION FROM SPOILED SWEET CLOVER: [3,3′-Methylene-Bis-(4-Hydroxycoumarin)] Which Prolongs Coagulation and Prothrombin Time of the Blood: A Clinical Study , 1942 .

[9]  J. Björkman,et al.  Melagatran, hirudin and heparin as adjuncts to tissue-type plasminogen activator in a canine model of coronary artery thrombolysis , 1997 .

[10]  J. Vacca,et al.  L-374,087, an efficacious, orally bioavailable, pyridinone acetamide thrombin inhibitor. , 1998, Bioorganic & medicinal chemistry letters.

[11]  R. D. Zeeuw.  Separation methods for drugs and related organic compounds, : by G. Schill, Apotekarsocieteten, Stockholm, 1st ed., 1978, VIII + 182 pp., price SKr. 75.00. , 1979 .

[12]  D. Janus,et al.  The discovery of orally available thrombin inhibitors: studies towards the optimisation of CGH1668. , 1998, Bioorganic & medicinal chemistry letters.

[13]  T. Müller,et al.  Profound and sustained inhibition of platelet aggregation by Fradafiban, a nonpeptide platelet glycoprotein IIb/IIIa antagonist, and its orally active prodrug, Lefradafiban, in men. , 1997, Circulation.

[14]  P. Held,et al.  Pharmacokinetics and Pharmacodynamics of Melagatran, a Novel Synthetic LMW Thrombin Inhibitor, in Patients with Acute DVT , 1999, Thrombosis and Haemostasis.

[15]  S. Chong,et al.  Argatroban analogs: Synthesis, thrombin inhibitory activity and cell permeability of aminoheterocyclic guanidine surrogates , 1994 .

[16]  J. Hirsh,et al.  Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. , 2001, Chest.

[17]  J. Lehmann.  HYPOPROTHROMBINÆMIA PRODUCED BY METHYLENE-BIS-(HYDROXYCOUMARIN): ITS USE IN THROMBOSIS , 1942 .

[18]  S. Pehrsson,et al.  Effects of Melagatran, a New Low-molecular-weight Thrombin Inhibitor, on Thrombin and Fibrinolytic Enzymes , 1998, Thrombosis and Haemostasis.

[19]  J. Deinum,et al.  The Importance of Enzyme Inhibition Kinetics for the Effect of Thrombin Inhibitors in a Rat Model of Arterial Thrombosis , 1997, Thrombosis and Haemostasis.

[20]  S. Carlsson,et al.  Antithrombotic effects and bleeding time of thrombin inhibitors and warfarin in the rat. , 1999, Thrombosis research.