Pharmacology

Bivalirudin is a bivalent DTI, i.e., it binds two distinct regions of thrombin: the active (catalytic) site and the fibrinogen-binding site. Moreover, like lepirudin and argatroban, bivalirudin binds to both free (soluble) and clot-bound (fibrin-bound) thrombin. It forms a 1:1 stoichiometric complex that neutralizes thrombin during coagulation and thrombus formation (Maraganore and Adelman, 1996). Thus, bivalirudin inhibits proteolytic cleavage of fibrinogen, thrombin-mediated activation of factors V, VIII, and XIII, and thrombin-induced platelet activation.

Bivalirudin (unlike lepirudin) is a reversible inhibitor of thrombin (Fig. 1). It acts initially as a non-competitive inhibitor, rendering thrombin inactive. Circulating proteases (including other thrombin molecules) slowly cleave bivalirudin near the amino-terminal end (between arg -pro ), thus eventually releasing the amino-terminal segment from the active site region of thrombin (Bates and Weitz, 1998; Carswell and Plosker, 2002; Reed and Bell, 2002; Sciulli and Mauro, 2002). This allows thrombin to resume catalytic function.

As mentioned, bivalirudin also inhibits thrombin by the binding of its carboxy-terminal segment to the fibrinogen-binding site on thrombin. This occurs at the same time that the amino-terminal segment attaches to the active site, thus resulting in

Proteolytic cleavage Identical to residues 53-64 of lepirudin

0 0

Post a comment