Uehlinger D E, Schaedeli F, Kinzig M, Sörgel F, Frey F J
Department of Medicine, University of Berne, Switzerland.
Antimicrob Agents Chemother. 1996 Aug;40(8):1903-9. doi: 10.1128/AAC.40.8.1903.
The pharmacokinetic profile of fleroxacin was studied in eight noninfected patients receiving regular hemodialysis (four women and four men; mean age, 63 years; age range, 48 to 73 years). Dialysis clearances (mean +/- standard deviation) calculated from the amount of drug recovered in the dialysate exceeded those calculated from rates of extraction from plasma for fleroxacin (126 +/- 29 versus 73 +/- 11 ml/min) and its metabolite N-demethylfleroxacin (103 +/- 31 versus 72 +/- 15 ml/min) but not that for the metabolite fleroxacin N-oxide (100 +/- 25 versus 100 +/- 12 ml/min). Data were fitted to a two-compartment model over the total observation period of 8 days (six oral daily doses of 200 mg of fleroxacin on days 1 to 6 and hemodialysis treatments on day 1,3, and 6) by nonlinear mixed-effects modeling. The random variability of plasma fleroxacin concentrations was 13% about its prediction. The estimated metabolic clearance was 25 ml/min (coefficient of variation, 43%), and the calculated steady-state volume of distribution was 84 liters (coefficient of variation, 16%). The model was expanded for the two major metabolites by the addition of a two-compartment metabolite distribution. Formation clearances of N-demethylfleroxacin and fleroxacin N-oxide were estimated to be 54 and 33% of fleroxacin's metabolic clearance, respectively. The conclusions were as follows. Because of the slow metabolic clearance and intermittent dialysis treatment, steady-state conditions were not reached after 1 week of oral fleroxacin therapy, and there was relevant accumulation of fleroxacin as well as that of fleroxacin N-oxide in our patients with end-stage renal disease. We recommend that infected hemodialysis patients be treated with an initial oral dose of 400 mg of fleroxacin and then daily oral doses of 200 mg. One cannot recommend the treatment of this patient population with fleroxacin over prolonged time periods until more date about the levels of accumulation of fleroxacin and its metabolites in infected patients with renal disease are available.
在8名接受定期血液透析的未感染患者（4名女性和4名男性；平均年龄63岁；年龄范围48至73岁）中研究了氟罗沙星的药代动力学特征。根据透析液中回收的药物量计算的透析清除率（平均值±标准差）超过了根据血浆中提取率计算的氟罗沙星清除率（126±29对73±11 ml/分钟）及其代谢产物N-去甲基氟罗沙星清除率（103±31对72±15 ml/分钟），但未超过代谢产物氟罗沙星N-氧化物的清除率（100±25对100±12 ml/分钟）。在8天的总观察期内（第1至6天每天口服6次200 mg氟罗沙星，第1、3和6天进行血液透析治疗），通过非线性混合效应模型将数据拟合到二室模型。血浆氟罗沙星浓度的随机变异性约为其预测值的13%。估计的代谢清除率为25 ml/分钟（变异系数43%），计算的稳态分布容积为84升（变异系数16%）。通过添加二室代谢物分布模型扩展了两种主要代谢物的模型。N-去甲基氟罗沙星和氟罗沙星N-氧化物的生成清除率分别估计为氟罗沙星代谢清除率的54%和33%。结论如下。由于代谢清除缓慢且透析治疗间断，口服氟罗沙星治疗1周后未达到稳态，在我们的终末期肾病患者中氟罗沙星及其N-氧化物存在相关蓄积。我们建议感染的血液透析患者初始口服400 mg氟罗沙星，然后每日口服200 mg。在获得更多关于氟罗沙星及其代谢产物在感染肾病患者中蓄积水平的数据之前，不能建议对该患者群体长期使用氟罗沙星进行治疗。
