Subacute toxicity of a halogenated pyrrole hydroxymethylglutaryl-coenzyme A reductase inhibitor in Wistar rats.
Wistar rats received an hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, a halogenated pyrrole designated PD 123244-15, orally by gavage for 14 days at 10, 50, 150, 300, and 600 mg/kg. Doses of 150-600 mg/kg caused death and marked systemic toxicity involving stomach, esophagus, liver, gonads, lymphoid tissues, and skeletal muscle. Histopathologic findings included hyperkeratosis in esophagus and forestomach, increased hepatic mitotic activity, ovarian follicular necrosis, testicular atrophy and arrested spermatogenesis, and skeletal muscle necrosis and regeneration. Elevated serum aspartate aminotransferase correlated with muscle necrosis and hepatocellular damage. Marked systemic effects associated with high plasma concentrations were consistent with toxicity defined for other HMG-CoA reductase inhibitors, with the exception of pathologic alterations in the esophagus and ovaries. Direct mucosal irritation may have contributed to forestomach and esophageal lesions induced by this halogenated pyrrole.
Sigler
R E
RE
Parke-Davis Pharmaceutical Research Division, Pathology and Experimental Toxicology, Ann Arbor, Michigan 48105.
Dominick
M A
MA
McGuire
E J
EJ
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007642:Keratosis / Q000139:chemically induced; D008099:Liver / Q000187:drug effects; D008297:Male; D008798:Mevalonic Acid / Q000627:therapeutic use; D009336:Necrosis; D009374:Neoplasms, Experimental / Q000139:chemically induced / Q000201:enzymology; D009929:Organ Size / Q000187:drug effects; D011758:Pyrroles / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D013270:Stomach / Q000187:drug effects / Q000473:pathology; D013272:Stomach Diseases / Q000139:chemically induced
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; C083011:PD 123244-15; D008798:Mevalonic Acid