Tecarfarin: A New Oral Anticoagulant and the Characterization of its In Vitro Metabolism Using Rat, Dog, and Human Hepatocytes

Abstract

Tecarfarin is a novel compound being developed for oral anticoagulation therapy for the prophylaxis and treatment of thromboembolic complications associated with atrial fibrillation and other cardiac disorders. Like warfarin, tecarfarin inhibits vitamin K epoxide reductase and is equipotent to warfarin at inhibiting this enzyme. It is metabolized to a single inactive metabolite, ATI‐5900, by human esterases. We compared the biotransformation of tecarfarin in cryopreserved hepatocytes isolated from male rats, dogs and humans and assessed the formation of ATI‐5900. We also scanned for, but did not quantify, several potential Phase I and Phase II metabolites for which chemical standards were not available. In dog and human hepatocytes, metabolism of tecarfarin was much slower than in rat hepatocytes, with less than 20% converted to ATI‐5900 at the end of 6 hours. We did not detect the formation of Phase II metabolites in any of the hepatocyte preparations. These results were supported by experiments where tecarfarin was incubated with rat, dog and human liver microsomes. It is well known that the metabolism of warfarin is dependent on CYP2C9 which is associated with various polymorphisms and, as a consequence, variable elimination. In contrast, the metabolism of tecarfarin is dependent on the ubiquitous esterase enzyme superfamily and therefore, its elimination should be more predictable in vivo.