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.