Toxicokinetic study of norfloxacin-induced arthropathy in juvenile animals

Abstract

A toxicokinetic study of norfloxacin-induced arthropathy in juvenile animals was undertaken using nalidixic acid as a standard drug. Norfloxacin and nalidixic acid were subcutaneously administered to rats and rabbits, orally administered to dogs, and norfloxacin was orally dosed to monkeys once a day for 7 consecutive days. Of the dose levels tested, the minimum arthropathic doses of norfloxacin were 100, 25, and 50 mg/kg/day in rats, rabbits, and dogs, respectively. At these doses, the peak serum concentrations (Cmax) on Day 6 were 16.1, 9.73, and 5.11 micrograms/ml, and the areas under the serum concentration/time curve (AUC0----infinity) were 31.9, 22.9, and 26.2 micrograms.hr/ml, in respective animals. Monkeys showed no arthropathy with norfloxacin at doses of less than 500 mg/kg/day, at which the Cmax and AUC0----infinity were 15.6 micrograms/ml and 103 micrograms.hr/ml, respectively. The minimum arthropathic doses of nalidixic acid were 50, 100, and 25 mg/kg/day in rats, rabbits, and dogs, respectively. The Cmax and AUC0----infinity of nalidixic acid were higher than those of norfloxacin in all animals. Joint tissues took up more norfloxacin than nalidixic acid, but when arthropathy was present the articular cartilage concentrations of the two drugs were in the same range. The penetration of norfloxacin into the articular cartilage was the same regardless of the joint's anatomical locations, but differed among species, being highest in rats and lowest in monkeys. The Cmax and AUC0----infinity of norfloxacin in animals at their arthropathic doses were far higher than those measured clinically in children, whereas those of nalidixic acid in animals did not differ much from its clinical parameters.