© 1998 Oxford University Press
research-article |
Altered Hemostasis in Male Rats Following Administration of the ACAT Inhibitor SKF-99085
Department of Safety Assessment, SmithKline Beecham Pharmaceuticals King of Prussia, Pennsylvania 19406
Received February 26, 1998; accepted July 6, 1998
SKF-99085, an acyl-CoA:cholesterol acyltransferase (ACAT) was evaluated in male and female Sprague-Dawley rats at oral doses of 0, 10, 100, or 400 mg/kg/day for 6 months as part of the preclinical safety assessment of this drug candidate. In male rats given 400 mg/kg/day SKF-99085, hemorrhage and death were observed in males during the first month of the study, prompting collection of blood samples at weeks 6, 17, and 24 to monitor coagulation parameters. A dose-related increase in activated partial thromboplastin time (APTT) and Thrombotest clotting time (TCT) was observed in all male drug-treated groups. Mean APTT values for male rats given 10, 100, or 400 mg/kg/day were increased maximally to 17.5, 20.8, and 34.7 s (control, 15.4–16.0 s), and mean TCT values were increased to 86, 100, and >300 s (control, 71–74 s), respectively. Mean prothrombin times (PT) for male rats given 400 mg/kg/day were increased to 16.5 s (control, 12.9–13.1 s). Activities of factors n, VII, IX, and X were decreased in males at dosages of 10, 100, or 400 mg/kg/day. Factor V and Vm activities were unaffected. In summary, the drug-related hemorrhagic disorder observed in male rats given high doses of the ACAT inhibitor SKF 99085 was attributed to a reduction in the activity of vitamin-K-dependent coagulation factors. In contrast to humans and some other species, the APTT and TCT were more sensitive than the PT in detecting this effect.
Key Words: ACAT inhibitor; hemostasis; vitamin-K-dependent coagulation factor activity; Thrombotest clotting time.