Altered hemostasis in male rats following administration of the ACAT inhibitor SKF-99085

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 dr ug candidate. In male rats given 400 mg/kg/day SKF-99085, hemorrhage and de ath were observed in males during the first month of the study, prompting c ollection of blood samples at weeks 6, 17, and 24 to monitor coagulation pa rameters. A dose-related increase in activated partial thromboplastin time (APTT) and Thrombotest clotting time (TCT) was observed in all male drug-tr eated groups. Mean APTT values for male rats given 10, 100, or 400 mg/kg/da y 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/k g/day were increased to 16.5 s (control, 12.9-13.1 s). Activities of factor s II, VII, IX, and X were decreased in males at dosages of 10, 100, or 400 mg/kg/day. Factor V and VIII activities were unaffected. In summary, the dr ug-related hemorrhagic disorder observed in male rats given high doses of t he ACAT inhibitor SKF 99085 was attributed to a reduction in the activity o f vitamin-K-dependent coagulation factors. In contrast to humans and some o ther species, the APTT and TCT were more sensitive than the PT in detecting this effect. (C) 1998 Society of Toxicology.