Multiple-dose kinetics of pefloxacin was determined in 12 normal male subjects given 400 mg pefloxacin by iv 1 h-infusion every 12 h for 16 doses. Twelve other subjects (6 men and 6 women) were given 400 mg pefloxacin by mouth every 12 h for 18 doses. Plasma and urine concentrations of pefloxacin and its main metabolites (N-desmethyl pefloxacin or norfloxacin and pefloxacin N-oxide) were measured by high performance liquid chromatography. The bioavailability of pefloxacin was complete and plasma concentrations after iv or oral administration were similar. Pefloxacin was rapidly absorbed from the gastrointestinal tract and reached maximum plasma concentrations about 1 h after dosing. Pefloxacin elimination (T 1/2 beta) increased from 11.00 +/- 2.64 h after the first iv dose to 13.93 +/- 3.58 h after the last iv dose (P less than 0.01). Apparent total body clearance decreased from 148.5 +/- 47.6 to 106.9 +/- 39.2 ml/min (P less than 0.01) because of decreased non-renal clearance (apparent volume of distribution did not significantly change over the repeated pefloxacin administration). Similar results were obtained after repeated oral dosing. Renal clearance of pefloxacin was low (7.47 +/- 2.28 ml/min) indicating that non-renal clearance represents the major route of elimination of this quinolone. Urinary excretion of pefloxacin and N-desmethyl and N-oxide metabolites was approximately 31% of the pefloxacin dose and beta-elimination half-lives of these metabolites were very close to that of pefloxacin (13.34 +/- 2.72 h and 11.95 +/- 2.64 h respectively). Due to a possible saturable process in the metabolic pathway, some accumulation occurred during repeated iv or oral treatment (accumulation ratio = 1.37 +/- 0.20). These results show that concentrations of pefloxacin in excess of the minimum inhibitory concentrations for many important pathogens can be rapidly achieved in plasma and urine with the 400 mg bid regimen with both iv and oral routes.