Prophylactic treatment with norfloxacin was initiated in a group of pediatric patients undergoing renal transplantation who were receiving cyclosporine and were susceptible to recurrent urinary tract infections. At discharge from the hospital, the mean daily dose of cyclosporine needed to maintain trough cyclosporine blood levels of 150 to 400 ng/ml was 4.5 mg/kg/day for the patients who received norfloxacin compared with 7.4 mg/kg/day for patients who did not receive the antibiotic. This observation suggested that the clearance of cyclosporine was decreased by the concomitant use of norfloxacin. The effect of norfloxacin on specific drug-metabolizing cytochrome P450 isozymes in vitro was examined to determine if the metabolism and subsequent clearance of cyclosporine and possibly other drugs are altered through a metabolic interaction with norfloxacin. In human liver microsomes, the activity of cytochrome P4503A4, the isozyme that metabolizes cyclosporine in humans, was inhibited by norfloxacin. In rat liver microsomes, norfloxacin inhibited the activity of cytochrome P4503A2, the isozyme responsible for cyclosporine metabolism in this species, but did not alter the activity of the rat cytochrome P450 isozymes 1A, 2E1, and 4A1. The in vitro studies suggest that the lower cyclosporine dose required by pediatric patients who were given norfloxacin was caused by inhibition of the metabolism of cyclosporine.