Abstract
To ascertain the clinicopathological process underlying dysglycemia induced by the fluoroquinolone antibacterial gatifloxacin (GFLX), we orally administered 100 or 300 mg/kg/day to male clinically healthy (naive) or spontaneous type II (diabetic) Goto-Kakizaki rats for 15 days (days 1 to 15). Treatment of naive rats with GFLX led to decreased blood glucose concentrations at 100 mg/kg/day on day 1. In diabetic animals, markedly increased blood glucose concentrations were noted from 100 mg/kg/day on day 3, and all of the animals given 300 mg/kg/day died or were killed because of moribund conditions by day 9. In a glucose tolerance test, serum insulin concentrations decreased significantly in naive rats receiving 300 mg/kg/day. Microscopically, cytoplasmic vacuolations of the pancreatic islets were observed in naive rats receiving 300 mg/kg/day, and congestion and/or hemorrhage were additionally noted in diabetic rats given 100 mg/kg/day or more. In toxicokinetics with 100 mg/kg/day, AUC0-8 hr values for GFLX were higher in diabetic rats than in naive rats, and relatively high serum GFLX concentrations at 8 hr post-dose and extraordinarily high pancreatic GFLX concentrations were also observed in diabetic rats. These results demonstrate that hypoglycemia or hyperglycemia induced by GFLX is associated with higher distribution and retention of GFLX in the pancreas, leading to disturbed insulin secretion.
