Screening a novel class of anticoagulants for multi-organ toxicity using Fischer 344 rats: involvement of clinical and anatomic pathologists in the early drug development process.
BACKGROUND
Veterinary clinical and anatomic pathologists play a critical role in assessing the safety of new molecules. The process for evaluation of candidate molecules in drug discovery may vary markedly, depending on the unique characteristics of the compound class.


OBJECTIVE
The goal of this report is to describe the evaluation process for assessing the potential toxicity of 2 anticoagulant compounds that were representative of molecules tested in early screening studies in Fisher rats, and to use these studies as an example of the strategic approach used by veterinary pathologists in pharmaceutical safety assessment.


METHODS
Groups of 3 rats were given vehicle alone or one of several doses of compound A or B by oral gavage daily for 4 consecutive days. Survival; clinical signs; body and organ weight measurements; hematologic, coagulation, and clinical biochemical testing; and gross and histologic findings at necropsy were assessed. Transmission electron microscopy was used to characterize unique findings in the liver of rats treated with compound B.


RESULTS
Both compounds caused dose-dependent prolongation of the prothrombin time (PT), activated partial thromboplastin time (APTT), and thrombin clotting time (TCT). Hepatobiliary and intestinal toxicity were identified by alterations in serum chemistry data, and by histopathologic findings. Electron microscopy and tissue inorganic phosphorus analysis revealed phospholipidosis in rats treated with compound B.


CONCLUSIONS
Pharmacologically mediated or "on target" effects for these molecules were characterized by dose-progressive prolongation of the PT, APTT, and TCT. Nonpharmacologically mediated or "off-target" toxicity consisted of hepatoxicity and enterotoxicity. These liabilities required that scientists alter the original molecular scaffold to reach the desired therapeutic target and minimize toxicity.
Schultze
A Eric
AE
Department of Pathology, Eli Lilly and Company, Lilly Reesearch Laboratories, Greenfield, IN, USA. aes@lilly.com
Sullivan
John M
JM
D000311:Adrenal Glands / Q000187:drug effects / Q000473:pathology; D000818:Animals; D000925:Anticoagulants / Q000633:toxicity*; D001777:Blood Coagulation / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D005260:Female; D007422:Intestines / Q000187:drug effects / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000473:pathology; D010341:Pathology, Veterinary; D051381:Rats; D011916:Rats, Inbred F344; D013950:Thymus Gland / Q000187:drug effects / Q000473:pathology; D018634:Veterinarians
D000925:Anticoagulants