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Altered hemostasis in male rats following administration of the ACAT inhibitor SKF-99085
Abstract:
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 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 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.
Insights
The ACAT inhibitor SKF-99085 caused bleeding and death in male rats by reducing vitamin-K-dependent clotting factors. Activated partial thromboplastin time and Thrombotest clotting time were sensitive indicators of this drug-induced hemorrhagic disorder.
Area of Science:
- Pharmacology
- Toxicology
- Biochemistry
Background:
- Acyl-CoA:cholesterol acyltransferase (ACAT) inhibitors are investigated for therapeutic potential.
- Preclinical safety assessments are crucial for drug candidates like SKF-99085.
Purpose of the Study:
- To evaluate the preclinical safety of SKF-99085, an ACAT inhibitor, in Sprague-Dawley rats.
- To investigate the effects of SKF-99085 on coagulation parameters and identify potential drug-related adverse effects.
Main Methods:
- Male and female Sprague-Dawley rats received oral doses of SKF-99085 (0, 10, 100, 400 mg/kg/day) for 6 months.
- Coagulation parameters, including activated partial thromboplastin time (APTT), Thrombotest clotting time (TCT), and prothrombin time (PT), were monitored.
- Activities of coagulation factors II, VII, IX, X, V, and VIII were assessed.
Main Results:
- Hemorrhage and death occurred in male rats at 400 mg/kg/day.
- A dose-related increase in APTT and TCT was observed in all male drug-treated groups.
- Activities of vitamin-K-dependent factors (II, VII, IX, X) were decreased in males, while factors V and VIII remained unaffected.
Conclusions:
- SKF-99085 induced a hemorrhagic disorder in male rats, linked to reduced activity of vitamin-K-dependent coagulation factors.
- APTT and TCT were more sensitive than PT in detecting the anticoagulant effects of SKF-99085 in this rat model.
- These findings highlight species-specific differences in drug response and the importance of comprehensive coagulation monitoring.
