Pharmacokinetics and pharmacodynamics of neutrophil-associated ciprofloxacin in humans
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P L Capecchi1, P Blardi, A De Lalla
1Institute of Clinical Medicine, University of Siena, School of Medicine, Italy.
Objective:
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 chemiluminescence generation induced by formyl-methionyl-leucyl-phenylalanine (fMLP) and platelet-activating factor (PAF) were studied ex 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. Cytosolic free calcium levels ([Ca2+]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 generation induced by the stimulating agents increased significantly, reaching a peak after 12 hours (+116% [p < 0.001] for fMLP and +66% [p < 0.05] for PAF). Similarly, chemiluminescence production showed a threefold increase in the response to the stimulating agents 12 hours after drug administration (p < 0.001). The increase in [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 chemiluminescence 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).
Conclusions:
Ciprofloxacin administration induced a long-lasting enhancement of PMN reactivity to fMLP and PAF. The levels of the drug in the cells were greater and more sustained in the time than those in plasma.
Insights
Ciprofloxacin antibiotic enhances polymorphonuclear leukocyte (PMN) reactivity long-term. Drug levels are higher and sustained longer within PMNs compared to plasma, impacting cell function.
Area of Science:
- Pharmacology
- Immunology
- Cell Biology
Background:
- Polymorphonuclear leukocytes (PMNs) are crucial immune cells.
- Antibiotic penetration into immune cells can alter their function.
- Ciprofloxacin is a widely used antibiotic.
Purpose of the Study:
- To investigate if ciprofloxacin penetration into PMNs affects their reactivity.
- To analyze the relationship between ciprofloxacin concentration in PMNs and plasma and PMN function.
Main Methods:
- Ex vivo study on 12 healthy volunteers.
- Measured superoxide anion and chemiluminescence generation induced by fMLP and PAF.
- Evaluated cytosolic free calcium levels ([Ca2+]i).
- Compared PMN reactivity with ciprofloxacin kinetics in plasma and PMNs.
Main Results:
- Ciprofloxacin significantly enhanced PMN superoxide generation and chemiluminescence production peaking at 12 hours.
- Increased [Ca2+]i in stimulated PMNs was significantly potentiated.
- Ciprofloxacin concentration in PMNs was higher and sustained longer than in plasma.
Conclusions:
- Ciprofloxacin administration leads to a prolonged enhancement of PMN reactivity.
- Higher and more sustained intracellular drug concentrations contribute to altered PMN function.