Pharmacokinetics and pharmacodynamics of neutrophil-associated ciprofloxacin in humans

✍ Scribed by Capecchi, Pier Leopoldo; Blardi, Patrizia; De Lalla, Arianna; Ceccatelli, Linda; Volpi, Luciana; Pasini, Franco Laghi; Di Perri, Tullio

• Publisher: Nature Publishing Group
• Year: 1995
• Tongue: English
• Weight: 865 KB
• Volume: 57
• Category: Article
• ISSN: 0009-9236
• DOI: 10.1016/0009-9236(95)90215-5

✦ Synopsis

Object&e: To study the possibility that the penetration of the antibiotic ciprofloxacin into polymorphonuclear leukocytes (PMN) may be associated with some changes in cell reactivity. Design: Superoxide anion and chemkminescence generation induced by formyl-methionyl-leucylphenylalanine (fMLP) and platelet-activating factor (PAP) were studied ex vivo in 12 healthy volunteers (mean age, 53.15 + 16.3 years; mean body weight, 71.23 f 6.9 kg) at tixed intervals up to 72 hours from the administration of a single oral dose of 250 mg ciprofloxacin. Cytosolic free calcium levels ([Ca"+]i) in resting and stimulated cells were also evaluated. The dynamic parameters of the effects on PMNs were compared with the kinetic profile of the drug in plasma and in PMNs. Results: Superoxide ge%neration induced by the stimulating agents increased signifkantiy, reaching a peak after 12 hours (+ 116% [p < O.OOl] for fMLP and + 66% [p < 0.051 for PAP). Similarly, chemiluminescence production showed a threefold increase in the response to the stimuiating agents 12 hours after drug administration ,@ < 0.001). The increase in [Ca"+]i in stimulated l?MNs was signifkantiy potentiated @ < 0.001). The mathematic analysis of the effects of ciprofloxacin showed that time to maximal activity was between 10.4 hours (PAP-dependent [Ca"+]i increase), and 15 hours (fMLl?-induced superoxide anion and chemiltiescence production). The ratio of PMNs to plasma ciprofloxacin concentration increased progressively, from 0.5 at 30 minutes to 10.4 after 24 hours. In addition, time to maximal activity and half-life differed in PMNs and in plasma (4.66 versus 1.90 hours and 13.03 versus 7.28 hours, respectively). Concluskms: Ciprofloxacin administration induced a long-lasting enhancement of PMN reactivity to tMLP and PAP. The levels of the drug in the cells were greater and more sustained in the time than those in plasma. (CLm P HARMACOL %ER 1995;57:446-54.