Epididymal and systemic phospholipidosis in rats and dogs treated with the dopamine D3 selective antagonist PNU-177864.
Repeat dose oral toxicity studies were conducted in rat and dog to assess the safety for human clinical testing of the potent dopamine D3 receptor antagonist, PNU-177864. Systemic phospholipidosis was the principal treatment-related change with epididymal epithelial cell phospholipidosis being the most prominent finding in rats and dogs. Epididymal epithelial cells had no histologic evidence of degeneration; sperm density and morphology were normal histologically in both species; and sperm concentration, morphology, and motility in the dog were comparable to dogs given vehicle. Other sites with phospholipidosis included lymphoid tissues (lymph nodes, Peyer's patches, and/or spleen), pulmonary alveolar macrophages, and peripheral blood lymphocytes in rats and dogs and adrenal cortex, liver, pituitary, hair follicles, bone marrow lymphocytes and plasma cells, and skeletal muscle in rats only. The phospholipidosis was resolved after a 6-week recovery period in all tissues but epididymis. There was no evidence of cell injury in tissues that had phospholipid accumulations except in rat skeletal muscle that had multifocal myofiber degeneration and necrosis. For clinical trials, serum AST and CK and peripheral blood lymphocyte vacuolation were considered potential safety biomarkers for skeletal muscle degeneration and phospholipidosis, respectively.
Rudmann
Daniel G
DG
Pathology Sciences/Services, Global Drug Safety Evaluation, Pfizer Inc., 7000 Portage Road, Kalamazoo, Michigan 49009, USA. rudmanng@lilly.com
McNerney
Mary E
ME
VanderEide
Stacey L
SL
Schemmer
Joyce K
JK
Eversole
Robert R
RR
Vonderfecht
Steven L
SL
D000818:Animals; D015415:Biomarkers; D004285:Dogs; D018492:Dopamine Antagonists / Q000633:toxicity*; D004353:Drug Evaluation, Preclinical; D004822:Epididymis / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D008064:Lipidoses / Q000139:chemically induced*; D008214:Lymphocytes / Q000187:drug effects / Q000473:pathology; D008297:Male; D008854:Microscopy, Electron; D018482:Muscle, Skeletal / Q000187:drug effects / Q000473:pathology; D010743:Phospholipids; D051381:Rats; D013045:Species Specificity; D013081:Sperm Motility / Q000187:drug effects; D013094:Spermatozoa / Q000187:drug effects; D014617:Vacuoles / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure
D015415:Biomarkers; D018492:Dopamine Antagonists; D010743:Phospholipids