Dagrosa E E, Verho M, Malerczyk V, de Looze S, Hajdú P, Toyodera K
Clin Ther. 1986;8(6):632-45.
Twelve healthy male volunteers received 14 oral doses of ofloxacin (300 mg each), and the concentrations of the unchanged drug were measured at various times in serum and urine over a period of 15 days. Serum and urine ofloxacin concentrations were determined in specific assays using high-pressure liquid chromatography (HPLC); urine levels were also determined by means of a microbiological assay. A washout period of 72 hours followed the first and 14th doses, allowing comparison of serum pharmacokinetics at the beginning and end of the multiple-dose regimen. Doses 2 to 14 were administered at 12-hour intervals. Maximum serum concentration (Cmax), concentration at 12 hours after dosing (C12), and area under the serum concentration-time curve (0 to 72 hours) were all 1.3 to 1.7 times greater after the 14th dose than after the initial dose. A 1.6-fold increase in C12 was already evident after the third dose; C12 remained more or less constant thereafter. Thus it is concluded that ofloxacin rapidly attained steady-state serum levels under a multiple-dose regimen, at levels only slightly above those following a single dose. High serum Cmax levels (4.6 and 5.9 micrograms/ml after the first and 14th doses, respectively) and long serum half-lives (6.0 and 7.3 hours after the first and last doses, respectively) indicated long-lasting, clinically relevant serum ofloxacin concentrations after oral administration. Serum ofloxacin levels 24 hours after the last dose were in the range of 0.3 to 0.7 microgram/ml, above the minimal inhibitory concentration (MIC90) for most bacterial strains. Cumulative urinary recovery remained high throughout the study. After 14 doses of ofloxacin (total, 4.2 gm), 88% of the unchanged drug was recovered in the urine; urinary concentrations remained above 1 microgram/ml, far above the MIC90 for most bacterial strains, for at least 108 hours after the final dose. High renal clearance values relative to total clearance (98%) confirmed the importance of the renal elimination route. Determinations of ofloxacin in urine using a microbiological assay were in close agreement with the HPLC determinations for all samples obtained throughout the study. Thus no detectable appearance of active metabolites occurred under the multiple-dose regimen. Ofloxacin was well tolerated; mild, probably drug-induced side effects were reported by three subjects, but they did not require any countermeasures.
12名健康男性志愿者口服了14剂氧氟沙星（每剂300毫克），并在15天内的不同时间测量了血清和尿液中未变化药物的浓度。血清和尿液中的氧氟沙星浓度通过高压液相色谱法（HPLC）的特定检测方法测定；尿液水平也通过微生物检测法测定。在第一剂和第14剂后有72小时的洗脱期，以便比较多剂量给药方案开始和结束时的血清药代动力学。第2至14剂以12小时间隔给药。第14剂后的最大血清浓度（Cmax）、给药后12小时的浓度（C12）以及血清浓度 - 时间曲线下面积（0至72小时）均比初始剂量后高1.3至1.7倍。第三剂后C12已经明显增加了1.6倍；此后C12大致保持不变。因此得出结论，在多剂量给药方案下，氧氟沙星能迅速达到稳态血清水平，其水平仅略高于单剂量给药后的水平。高血清Cmax水平（第一剂和第14剂后分别为4.6和5.9微克/毫升）和长血清半衰期（第一剂和最后一剂后分别为6.0和7.3小时）表明口服给药后血清中氧氟沙星浓度具有持久的临床相关性。最后一剂后24小时的血清氧氟沙星水平在0.3至0.7微克/毫升范围内，高于大多数细菌菌株的最低抑菌浓度（MIC90）。在整个研究过程中，尿液中药物的累积回收率一直很高。服用14剂氧氟沙星（总计4.
