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.
|
Authors | T Sellers, S O'Brien, K Gossett, M Gunning, D Boram, S Rehm, W Kerns |
Journal | Toxicological sciences : an official journal of the Society of Toxicology
(Toxicol Sci)
Vol. 46
Issue 1
Pg. 151-4
(Nov 1998)
ISSN: 1096-6080 [Print] United States |
PMID | 9928678
(Publication Type: Journal Article)
|
Chemical References |
- Anticholesteremic Agents
- Diphosphonates
- Enzyme Inhibitors
- SK&F 99085
- Vitamin K
- Acetyl-CoA C-Acyltransferase
|
Topics |
- Acetyl-CoA C-Acyltransferase
(antagonists & inhibitors)
- Animals
- Anticholesteremic Agents
(toxicity)
- Diphosphonates
(toxicity)
- Enzyme Inhibitors
(toxicity)
- Female
- Hemorrhage
(chemically induced, pathology)
- Hemostasis
(drug effects)
- Male
- Partial Thromboplastin Time
- Prothrombin Time
- Rats
- Rats, Sprague-Dawley
- Vitamin K
(physiology)
|