MULTIPLE-DOSE PHARMACOKINETICS OF SPARFLOXACIN AND ITS INFLUENCE ON FECAL FLORA

In a randomized, double-blind, placebo-controlled, multiple-dose pharmacokinetic study, the safety and effect on intestinal flora of sparfloxacin (SPX) were determined in 12 healthy male volunteers (8 received SPX and 4 received a placebo). Following fasting and oral administration of 400 mg on day 1 and 200 mg on days 2 to S, concentrations of the free drug in serum, urine, and feces were measured by high-performance liquid chromatography; serum and urine were also evaluated by a microbiological assay. All results, except those for renal excretion, exclude the glucuroconjugate metabolite. A mean peak concentration in serum (400-mg dose) of 0.56 +/- 0.13 mg/liter was measured 3.52 +/- 0.98 h after administration. Pharmacokinetic parameters (measured by high-performance liquid chromatography) were based on an open, one-compartment model and resulted in the following day 1 (calculated for the 200-mg dose), day 4 (recalculated for a single dose), and day 8 values (mean +/- standard deviation): area under the curve, 16.4 +/- 2.3 (day 1) and 18.3 +/- 5.1 (day 4) mg h/liter; elimination half-life, 18.3 +/- 3.9 h; steady-state volume of distribution, 4.7 +/- 1.4 (day 1) and 4.3 +/- 1.2 (day 8) liters/kg; apparent total clearance, 201 +/- 31 (day 1) and 190 +/- 51 (day 4) ml/min; renal clearance, 19.1 +/- 5.8 (day 1) and 23.2 +/- 19.4 (day 4) ml/min. Recovery in urine on day 1 was 5.89% +/- 1.4% of the dose in 24 h for the parent compound and 18.4% +/- 6.8% for the SPX glucuronide. The concentrations of SPX in stool declined from 759.6 +/- 484.4 mg/kg on day 2 and 671.7 +/- 474.8 mg/kg on day 4 to 476.4 +/- 239.7 mg/kg on day 8. These results demonstrate moderate-to-good bioavailability of SPX in addition to a long elimination half-life, a high volume of distribution, and mainly nonrenal elimination. The fecal flora was analyzed for aerobic and anaerobic bacteria before, during, and after drug administration. SPX resulted in a decrease of Escherichia coli, a moderate decrease of enterococci, and a slight decrease of bifidobacteria. Except for E. coli, the numbers of fecal bacteria returned to pretreatment values by day 28 after first dosing. Overall tolerance of SPX was good. Adverse reactions in volunteers were mild and self-limited and were as follows in the SPX-treated group: gastrointestinal disturbances, four cases; soft stool, two cases; pruritus, one case; mild cephalgia, three cases. No gastrointestinal disturbances were noted in the placebo-treated group; side effects in this group were as follows: mild cephalgia, one case; transient myalgia, one case.