Pharmacokinetic and pharmacodynamic interactions between intravenous ciprofloxacin and oral ferrous sulfate

Changes in oral bioavailability and in vitro antimicrobial activity have be en the focus of many previous interaction studies for metal cations and qui nolones. This study is the first to examine the possibility of an interacti on in the systemic circulation using ciprofloxacin and ferrous sulfate as r epresentative interactants in a rat model, and to determine the changes, if any, in the pharmacokinetics and pharmacodynamics of the antibiotic. To mi nimize direct physical interaction in the gastrointestinal (GI) tract, the current study design required the male Sprague Dawley rats (220-240 g) to b e dosed with 100 mg/kg of oral ferrous sulfate and 5 mg/kg of intravenous c iprofloxacin, Control animals received only intravenous ciprofloxacin, Bloo d and urine samples were collected over time for quantitation of ciprofloxa cin independently by both HPLC (H) and microbiological (M) assays. Results showed that the disposition of ciprofloxacin in control animals was biexpon ential 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 d istribution and a longer elimination of ciprofloxacin; mean V-d,V-lambda z and t(1/2,lambda z) estimates increased by 2- and 4-fold, respectively. Rel ative to controls, antibiotic exposure (AUC(0-infinity)) was also significa ntly higher (p<0.05) in the presence of iron (1.89+/-0.15 vs. 1.00+/-0.39 m g/h/L), A strong assay dependency was observed for ciprofloxacin concentrat ions observed post-distribution; the respective M/H ratios for AUC(0-infini ty) 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 a ctivity was in clear contrast to the higher exposure and longer t(1/2,lambd a z) of the antibiotic. In conclusion, concomitant oral iron dosing induced significant changes in the pharmacokinetics/pharmacodynamics of intravenou s ciprofloxacin.