Fischman A J, Livni E, Babich J, Alpert N M, Liu Y Y, Thom E, Cleeland R, Prosser B L, Callahan R J, Correia J A
Department of Radiology, Massachusetts General Hospital, Boston.
Antimicrob Agents Chemother. 1992 Oct;36(10):2286-92. doi: 10.1128/AAC.36.10.2286.
18F-labeled fleroxacin was used to measure the pharmacokinetics of fleroxacin in healthy and infected animals by positron emission tomography (PET) and tissue radioactivity measurements. In all experiments, a pharmacological dose of unlabeled drug (10 mg/kg) was coinjected with the tracer. The pharmacokinetics of [18F]fleroxacin was measured in groups of healthy mice (n = six per group) at 10, 30, 60, and 120 min after injection and in groups of rats with Escherichia coli thigh infections (n = six per group) at 60 and 120 min after injection by radioactivity measurements in excised tissues. In healthy rabbits (n = 4) and in rabbits with E. coli thigh infections (n = 4), tissue concentrations of drug were determined by serial PET imaging over 2 h; after the final image was acquired, animals were sacrificed and concentrations measured by PET were compared with the results of tissue radioactivity measurements. In all three species, there was rapid equilibration of [18F]fleroxacin to significant concentrations in most peripheral organs; low concentrations of drug were detected in the brain. Accumulations of radiolabeled drug in infected and healthy thigh muscles were similar. Peak concentrations of drug of more than three times the MIC for 90% of members of the family Enterobacteriaceae (greater than 100-fold for most organisms) were achieved in all tissues except brain and remained above this level for more than 2 h. Especially high peak concentrations were achieved in the kidney (greater than 75 micrograms/g), liver (greater than 50 micrograms/g), blood (greater than 25 micrograms/g), and bone and lung (greater than 10 micrograms/g). Since the MICs for 90% of all Enterobacteriaceae are <2 micrograms/ml, fleroxacin should be particularly useful in treating gram-negative infections affecting these tissues. In contrast, the low concentration of drug delivered to the brain should limit the toxicity of the drug for the central nervous system.
用18F标记的氟罗沙星，通过正电子发射断层扫描（PET）和组织放射性测量，来测定氟罗沙星在健康动物和感染动物体内的药代动力学。在所有实验中，将药理剂量的未标记药物（10mg/kg）与示踪剂一起注射。通过在注射后10、30、60和120分钟对健康小鼠组（每组n = 6）进行放射性测量，以及在注射后60和120分钟对患有大肠杆菌大腿感染的大鼠组（每组n = 6）进行切除组织的放射性测量，来测定[18F]氟罗沙星的药代动力学。在健康兔（n = 4）和患有大肠杆菌大腿感染的兔（n = 4）中，通过2小时的连续PET成像来测定药物的组织浓度；在获取最终图像后，处死动物，并将PET测量的浓度与组织放射性测量结果进行比较。在所有这三个物种中，[18F]氟罗沙星在大多数外周器官中迅速平衡至显著浓度；在脑中检测到低浓度的药物。放射性标记药物在感染和健康大腿肌肉中的蓄积相似。除脑外，所有组织中药物的峰值浓度均超过肠杆菌科90%成员的最低抑菌浓度（MIC）的三倍以上（大多数微生物超过100倍），并在该水平以上保持超过2小时。在肾脏（大于75微克/克）、肝脏（大于50微克/克）、血液（大于25微克/克）以及骨骼和肺部（大于10微克/克）中达到特别高的峰值浓度。由于所有肠杆菌科90%成员的MIC均<2微克/毫升，氟罗沙星在治疗影响这些组织的革兰氏阴性感染方面应特别有用。相比之下，输送到脑的药物浓度较低，这应会限制该药物对中枢神经系统的毒性。
