In vitro and in vivo ciprofloxacin pharmacokinetics in human neutrophils

Abstract

Early in vitro investigations have shown that ciprofloxacin is concentrated within human neutrophils (polymorphonuclear leukocytes [PMNs]) at between 3 and 11 times the extracellular concentration. The elution of ciprofloxacin from cells is relatively rapid when the extracellular concentration is reduced. In order to estimate the in vivo intracellular penetration of ciprofloxacin and to determine its intracellular pharmacokinetics' PMNs were recovered from blood samples drawn from healthy volunteers at different times during a 24-h period after they were given a 750-mg oral dose. High-performance liquid chromatographic determination of ciprofioxacin in serum and'cells showed that the intracellular/serum ratio was 3.7 at 1.5 h (maximum concentration of drug in serum), 5.7 at 12 h, and 20 at 24 h. The area under the curve ratio was 3.73. The mean ehimination half-lives of ciprofloxacin were 3.7 and 6.2 h in serum and PMNs, respectively. These data show that in vivo findings are in agreement with in vitro findings. The large uptake of ciprofloxacin by PMNs combined with a prolonged intracellular half-life described under the conditions of human therapy should provide the basis for the use of ciprofloxacin in infections caused by susceptible intracellular bacteria.Fluoroquinolones represent a new group of compounds that exhibit very high activity against a broad spectrum of bacteria, including those that develop intracellularly and that have important extravascular diffusion. Moreover, among the currently marketed compounds, ciprofloxacin has the lowest MICs and the greatest apparent volume of distribution. Thus, it should be one of the most promising agents for the treatment of intracellular infections. Because the ability of an antimicrobial agent to penetrate into phagocytic cells is the first essential step for activity against facultative intracellular organisms (7), in this study we examined the ability of ciprofloxacin to enter human polymorphonuclear leukocytes (PMNs). The uptake of ciprofloxacin by several cell types has been studied previously. These were in vitro experiments only (2, 3), i.e., they were done under experimental conditions, which is very different from the in vivo interactions between the antibiotic and cells. However, these data can be considered very informative, and they demonstrate that ciprofloxacin has a high degree of intracellular penetration followed by a rapid release into the extracellular medium. At present, no information regarding the intracellular behavior of ciprofloxacin in patients receiving the drug has been published.The purpose of this study was to determine whether the pattern of ciprofloxacin penetration into cells observed in vivo corroborates the in vitro data and which findings might be made regarding the clinical use of ciprofloxacin. MATERIALS AND METHODSThe first part of this study was devoted to characterization of the principal parameters of ciprofloxacin penetration into human PMNs in vitro. Following this, the drug was administered to humans and the intracel...

Accumulation of a newly developed fluoroquinolone, OPC-17116, by human polymorphonuclear leukocytes

“…Relatively high I/E ratios of between 2 to 8 have been demonstrated for the new quinolones (2,8), with OFLX having the highest ratio at about 8. This study showed the I/E ratios of LVFX and DR-3354 to be similar to that of OFLX, although the ratio of LVFX was slightly higher than those of DR-3354 and OFLX.…”

Lung Tissue Distribution After Intravenous Administration of Grepafloxacin: Comparative Study With Levofloxacin

“…In the studies, which evaluated the penetration of various antimicrobial agents into human polymorphonuclear leukocytes, new quinolones have relative high intra/ extracellular ratios of between 2 to 8 in drug concentrations (6,16). LVFX also showed high intra/extracellular ratios of 9.8 ± 0.9 in neutrophils.…”

Accumulation of Ciprofloxacin and Minocycline by Cultured Human Gingival Fibroblasts

“…The latter was measured by equilibrating fibroblast suspensions with [ 3 H]-water (5 μCi/ml, NEN Life Science Products) (Garraffo et al, 1991). After incubation for 10 minutes, cells were rapidly pelleted through oil as previously described (Walters et al, 1999).…”

“…Since polymorphonuclear leukocytes (PMNs) take up and accumulate ciprofloxacin and other fluoroquinolones (Easmon and Crane, 1985;Perea et al, 1992;Garraffo et al, 1991), it has been suggested that they might carry ciprofloxacin with them as they migrate to inflamed periodontal sites. In support of this hypothesis, recent studies demonstrated that root planing results in a small (10%), but statistically significant, decrease in GF ciprofloxacin levels at sites that initially exhibit inflammation.…”