SUBACUTE TOXICITY OF A HALOGENATED PYRROLE HYDROXYMETHYLGLUTARYL-COENZYME-A REDUCTASE INHIBITOR IN WISTAR RATS

Wistar rats received an hydroxymethylglutaryl-coenzyme A (HMG-CoA) red uctase inhibitor, a halogenated pyrrole designated PD 123244-15, orall y by gavage for 14 days at 10, 50, 150, 300, and 600 mg/kg. Doses of 1 50-600 mg/kg caused death and marked systemic toxicity involving stoma ch, esophagus, liver, gonads, lymphoid tissues, and skeletal muscle. H istopathologic findings included hyperkeratosis in esophagus and fores tomach, increased hepatic mitotic activity, ovarian follicular necrosi s, testicular atrophy and arrested spermatogenesis, and skeletal muscl e necrosis and regeneration. Elevated serum aspartate aminotransferase correlated with muscle necrosis and hepatocellular damage. Marked sys temic effects associated with high plasma concentrations were consiste nt 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 esop hageal lesions induced by this halogenated pyrrole.