Pharmacokinetics and tolerance of ciprofloxacin after sequential increasing oral doses

The pharmacokinetics and safety of orally administered ciprofloxacin (Bay o 9867) were examined in 12 healthy male volunteers who received sequential doses of 250, 500, 750, and 1,000 mg. The individual and mean data were best described by biexponential disposition and elimination, assuming an apparent zero-order rate of absorption. The peak serum concentrations determined from the individual data occurred at approximately 1.5 h after each dose and ranged from 0.42 to 4.2 micrograms/ml; the mean peak concentrations increased in proportion to the dose. The areas under the curve determined from the mean data were also proportional with respect to dose. The mean elimination half-lives calculated from pooled data were 4.1, 4.1, 6.9, and 6.3 h for doses of 250, 500, 750, and 1,000 mg, respectively. Longer half-lives but proportional area-under-the-curve values after the 750- and 1,000-mg doses implied that smaller fractions of ciprofloxacin were absorbed after these doses, although nonlinear kinetics could not be ruled out. The mean serum concentrations 12 and 24 h following each dose were greater than or equal to 0.08 and 0.01 micrograms/ml, respectively. The urinary concentrations ranged from 30 to 500 micrograms/ml for at least 12 h after administration and were greater than or equal to 9 micrograms/ml at 24 h following each dose. The urinary recovery level of unchanged ciprofloxacin over a 24-h period ranged from 28 to 44%. The mean renal clearances for each dose ranged from 300 to 500 ml/min. Ciprofloxacin was well tolerated, and no significant clinical or laboratory abnormalities were observed.