PHARMACOKINETICS AND PHARMACODYNAMICS OF NEUTROPHIL-ASSOCIATED CIPROFLOXACIN IN HUMANS

Objective: To study the possibility that the penetration of the antibi otic ciprofloxacin into polymorphonuclear leukocytes (PMN) may be asso ciated with some changes in cell reactivity. Design: Superoxide anion and chemiluminescence generation induced by formyl-methionyl-leucyl-ph enylalanine (fMLP) and platelet-activating factor (PAF) were studied e x vivo in 12 healthy volunteers (mean age, 53.15 +/- 16.3 years; mean body weight, 71.23 +/- 6.9 kg) at fixed intervals up to 72 hours from the administration of a single oral dose of 250 mg ciprofloxacin. Cyto solic free calcium levels ([Ca2+]i) in resting and stimulated cells we re also evaluated. The dynamic parameters of the effects on PMNs were compared with the kinetic profile of the drug in plasma and in PMNs. R esults: Superoxide generation induced by the stimulating agents increa sed significantly, reaching a peak after 12 hours (+116% [p < 0.001] f or fMLP and +66% [p < 0.05] for PAF). Similarly, chemiluminescence pro duction showed a threefold increase in the response to the stimulating agents 12 hours after drug administration (p < 0.001). The increase i n [Ca2+]i in stimulated PMNs was significantly potentiated (p < 0.001) . The mathematic analysis of the effects of ciprofloxacin showed that time to maximal activity was between 10.4 hours (PAF-dependent [Ca2+]i increase), and 15 hours (fMLP-induced superoxide anion and chemilumin escence production). The ratio of PMNs to plasma ciprofloxacin concent ration increased progressively, from 0.5 at 30 minutes to 10.4 after 2 4 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 ho urs, respectively). Conclusions: Ciprofloxacin administration induced a long-lasting enhancement of PMN reactivity to fMLP and PAF. The leve ls of the drug in the cells were greater and more sustained in the tim e than those in plasma.