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Thrombosis
Volume 2012 (2012), Article ID 560513, 6 pages
http://dx.doi.org/10.1155/2012/560513
Research Article

Reversible Crystallization of Argatroban after Subcutaneous Application in Pigs

1Laboratorio de Hemostasia y Genetica Vascular, Centro de Bioquimica y Biofisica, Instituto Venezolano de Investigaciones Cientificas (IVIC), Caracas 1020, Venezuela
2University Hospital Jena, Friedrich Schiller University Jena, Erlanger Allee 101, 07747 Jena, Germany

Received 2 May 2012; Accepted 17 July 2012

Academic Editor: Graham F. Pineo

Copyright © 2012 Mercedes Lopez and Goetz Nowak. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Argatroban is a thrombin inhibitor used as anticoagulant in patients with heparin-induced thrombocytopenia. It is usually administered as an intravenous bolus followed by infusion. Nevertheless, its pharmacokinetics after subcutaneous administration is unknown. The aim of this study was to assess the pharmacokinetics of two different formulations of argatroban in pigs after subcutaneous administration. Antithrombotic activity in plasma was determined by ecarin chromogenic assay. To visualize the formation of crystals, argatroban was administered to rats into the subcutaneous tissue exposed after removing the skin, and the injection site was photographed at different times. After subcutaneous administration of a sorbitol/ethanol formulation of argatroban in pigs was observed a slow absorption phase was followed by long-lasting levels of this inhibitor. 𝐶 m a x and A U C ( 0 2 4 ) showed dose-dependent increases, while elimination half-life and 𝑡 m a x value did not change significantly with dose. In contrast, saline-dissolved argatroban showed a faster absorption phase followed by a shorter elimination half-life. Argatroban dissolved in sorbitol/ethanol leads to long-lasting plasma levels due to the formation and permanent dissolution of a crystalline depot at the injection place. This represents a simple way to deliver argatroban continuously over an extended period which can be beneficial for prophylaxis or treatment of chronic coagulations disorders.