Effects of the direct thrombin inhibitor dabigatran and its orally active prodrug, dabigatran etexilate, on thrombus formation and bleeding time in rats.
Dabigatran is a reversible direct, selective thrombin inhibitor, undergoing clinical development as its orally active prodrug, dabigatran etexilate. The objective of this trial was to assess the antithrombotic and anticoagulant effects of dabigatran and dabigatran etexilate in a rat model of venous thrombosis. In order to do this a modified Wessler model was used to assess the antithrombotic and anticoagulant effects of intravenous (i.v.) dabigatran and oral dabigatran etexilate administration. In addition, a rat tail bleeding time model was used to investigate the antihemostatic effect of dabigatran. The study demonstrated that bolus administration of dabigatran (0.01-0.1 mg/kg) reduced thrombus formation dose-dependently, with an ED50 (50% of the effective dose) of 0.033 mg/kg and complete inhibition at 0.1 mg/kg. By comparison, ED50 values for heparin (0.03-0.3 mg/kg), hirudin (0.01-0.5 mg/kg) and melagatran (0.1-0.5 mg/kg) were 0.07, 0.15 and 0.12 mg/kg, respectively. Oral administration of dabigatran etexilate (5-30 mg/kg) inhibited thrombus formation in a dose- and time-dependent manner, with maximum inhibition within 30 min of pretreatment, suggesting a rapid onset of action. Following i.v. administration of dabigatran (0.1-1.0 mg/kg), a statistically significant prolongation of bleeding time was observed at doses at least 15- and 5-fold greater than ED50 and ED100 (100% of the effective dose) doses, respectively; there was no significant increase in bleeding tendency at the maximum therapeutically effective dose (0.1 mg/kg). It can be concluded that dabigatran and its oral prodrug, dabigatran etexilate, show promise in the management of thromboembolic disease.
Wienen
Wolfgang
W
Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany. wolfgang.wienen@bc.boehringer-ingelheim.com
Stassen
Jean-Marie
JM
Priepke
Henning
H
Ries
Uwe Joerg
UJ
Hauel
Norbert
N
D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage* / Q000494:pharmacology; D001562:Benzimidazoles / Q000008:administration & dosage* / Q000494:pharmacology; D001760:Bleeding Time; D000069604:Dabigatran; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D004353:Drug Evaluation, Preclinical; D011355:Prodrugs / Q000008:administration & dosage / Q000494:pharmacology; D011725:Pyridines / Q000008:administration & dosage* / Q000494:pharmacology; D051381:Rats; D013927:Thrombosis / Q000188:drug therapy / Q000517:prevention & control*
D000925:Anticoagulants; D001562:Benzimidazoles; D011355:Prodrugs; D011725:Pyridines; D000069604:Dabigatran