Pharmacokinetic and pharmacodynamic interactions between intravenous ciprofloxacin and oral ferrous sulfate

Changes in oral bioavailability and in vitro antimicrobial activity have been the focus of many previous interaction studies for metal cations and quinolones. This study is the first to examine the possibility of an interaction in the systemic circulation using ciprofloxacin and ferrous sulfate as representative interactants in a rat model, and to determine the changes, if any, in the pharmacokinetics and pharmacodynamics of the antibiotic. To minimize direct physical interaction in the gastrointestinal (GI) tract, the current study design required the male Sprague Dawley rats (220-240 g) to be dosed with 100 mg/kg of oral ferrous sulfate and 5 mg/kg of intravenous ciprofloxacin. Control animals received only intravenous ciprofloxacin. Blood and urine samples were collected over time for quantitation of ciprofloxacin independently by both HPLC (H) and microbiological (M) assays. Results showed that the disposition of ciprofloxacin in control animals was biexponential with a mean (+/-SD) terminal elimination half-life (t(1/2,lambda z)) of 0.93+/-0.30 h. A large apparent volume of distribution (V(d,lambda z): 6.96+/-1.56 L/kg) was observed. In addition, concentration vs. time profiles generated by both assays were similar. When the antibiotic was dosed with oral iron, parameter estimates generated by HPLC appeared to show a wider distribution and a longer elimination of ciprofloxacin; mean V(d,lambda z) and t(1/2,lambda z) estimates increased by 2- and 4-fold, respectively. Relative to controls, antibiotic exposure (AUC(0-infinity) was also significantly higher (p<0.05) in the presence of iron (1.89+/-0.15 vs. 1.00+/-0.39 mg/h/L). A strong assay dependency was observed for ciprofloxacin concentrations observed post-distribution; the respective M/H ratios for AUC(0-infinity) and urinary recovery were 1.1 and 0.9 for controls and 0.7 and 0.5 for animals receiving oral iron. This iron related reduction in antimicrobial activity was in clear contrast to the higher exposure and longer t(1/2,lambda z) of the antibiotic. In conclusion, concomitant oral iron dosing induced significant changes in the pharmacokinetics/pharmacodynamics of intravenous ciprofloxacin.