Pharmacokinetics of YM466, a new factor Xa inhibitor, in rats and dogs.

The pharmacokinetics of YM466, a selective inhibitor for factor Xa, was investigated after single intravenous and oral dosing to rats and dogs. After i.v. dosing, plasma YM466 concentration declined in a bi-phasic manner with a terminal elimination half-life of 1.4 h in rats and 0.8 h in dogs. Total plasma clearance values were 884 and 1212 ml/h/kg in rats and dogs, respectively. After oral dosing, plasma YM466 concentrations reached maximum within 2 h and increased in a dose-proportional manner in rats while increase was nonlinear in dogs. The absolute bioavailability of YM466 was 2.7-4.5% in rats, almost constant regardless of the dose levels investigated, while it was 6.9-24.6% in dogs, indicating nonlinear pharmacokinetics. The plasma protein binding of YM466 was 54.7-56.5% in rats and 45.2-49.0% in dogs and almost constant regardless of the concentration. No metabolism of YM466 was observed in an in vitro liver microsome study. These findings suggest that the low bioavailability of YM466 is attributable to the poor absorption not to the extensive metabolism.