Joukhadar Christian, Dehghanyar Pejman, Traunmüller Friederike, Sauermann Robert, Mayer-Helm Bernhard, Georgopoulos Apostolos, Müller Markus
Department of Clinical Pharmacology, Division of Clinical Pharmacokinetics, Vienna, Austria.
Antimicrob Agents Chemother. 2005 Oct;49(10):4149-53. doi: 10.1128/AAC.49.10.4149-4153.2005.
The present study addressed the effect of microcirculatory blood flow on the ability of ciprofloxacin to penetrate soft tissues. Twelve healthy male volunteers were enrolled in an analyst-blinded, clinical pharmacokinetic study. A single intravenous dose of 200 mg of ciprofloxacin was administered over a period of approximately 20 min. The concentrations of ciprofloxacin were measured in plasma and in the warmed and contralateral nonwarmed lower extremities. The microdialysis technique was used for the assessment of unbound ciprofloxacin concentrations in subcutaneous adipose tissue. Microcirculatory blood flow was measured by use of laser Doppler flowmetry. Warming of the extremity resulted in an increase of microcirculatory blood flow by approximately three- to fourfold compared to that at the baseline (P < 0.05) in subcutaneous adipose tissue. The ratio of the maximum concentration (C(max)) of ciprofloxacin for the warmed thigh to the C(max) for the nonwarmed thigh was 2.10 +/- 0.90 (mean +/- standard deviation; P < 0.05). A combined in vivo pharmacokinetic (PK)-in vitro pharmacodynamic (PD) simulation based on tissue concentration data indicated that killing of Pseudomonas aeruginosa (ATCC 27853 and two clinical isolates) was more effective by about 2 log(10) CFU/ml under the warmed conditions than under the nonwarmed conditions (P < 0.05). The improvement of microcirculatory blood flow due to the warming of the extremity was paralleled by an increased ability of ciprofloxacin to penetrate soft tissue. Subsequent PK-PD simulations based on tissue PK data indicated that this increase in tissue penetration was linked to an improved antimicrobial effect at the target site.
本研究探讨了微循环血流量对环丙沙星穿透软组织能力的影响。12名健康男性志愿者参与了一项分析师盲法临床药代动力学研究。静脉单次注射200mg环丙沙星，给药时间约20分钟。测定血浆以及温热和对侧未温热的下肢中环丙沙星的浓度。采用微透析技术评估皮下脂肪组织中未结合的环丙沙星浓度。使用激光多普勒血流仪测量微循环血流量。与基线相比，肢体温热导致皮下脂肪组织中的微循环血流量增加约三到四倍（P<0.05）。温热大腿中环丙沙星的最大浓度（C(max)）与未温热大腿的C(max)之比为2.10±0.90（平均值±标准差；P<0.05）。基于组织浓度数据的体内药代动力学（PK）-体外药效学（PD）联合模拟表明，在温热条件下对铜绿假单胞菌（ATCC 27853和两株临床分离株）的杀灭效果比未温热条件下约高2 log(10) CFU/ml（P<0.05）。由于肢体温热导致的微循环血流量改善与环丙沙星穿透软组织能力的增强同时出现。随后基于组织PK数据的PK-PD模拟表明，组织穿透力的增加与靶部位抗菌效果的改善有关。
