Target site concentrations of ciprofloxacin after single intravenous and oral doses

Abstract

To characterize the potential of ciprofloxacin penetration into human soft tissues following intravenous (i.v.) and oral (p.o.) administration, we measured the free ciprofloxacin concentrations in interstitial space fluid of skeletal muscle and subcutaneous adipose tissue by microdialysis. In addition, ciprofloxacin concentrations were measured in cantharis-induced skin blisters, saliva, and capillary plasma and were compared to the total concentrations in venous plasma. Furthermore, a pharmacodynamic in vitro model was used to simulate in vivo pharmacokinetics in bacterial culture. Eight healthy volunteers received ciprofloxacin in an open randomized crossover fashion either as a single i.v. infusion of 400 mg over 60 min or as a single p.o. dose of 500 mg. For both tissues the mean areas under the concentration-time curves (AUCs) for interstitial space fluid (AUC(interstitial fluid)s) were significantly lower than the corresponding AUC(plasma)s, with AUC(interstitial fluid)/AUC(plasma) ratios ranging from 0.38 to 0.68. For skeletal muscle, the AUC(interstitial fluid) was significantly higher after administration of 400 mg i.v. than after administration of 500 mg p.o., with a ratio of the AUC after p.o. administration/AUC after i.v. administration of 0.64. The ratio of the concentration in skeletal muscle/concentration in plasma increased over the entire observation period, implying that ciprofloxacin concentrations were not at steady state. The ratio of the concentration in skin blister fluid/concentration in plasma reached values above 4, indicating a preferential penetration of ciprofloxacin into inflamed lesions. The concentrations in saliva and capillary blood were similar to the corresponding total levels in plasma. In vitro both in vivo ciprofloxacin concentration-time profiles were equally effective against select bacterial strains. In conclusion, single-dose administration of two bioequivalent dosage forms of ciprofloxacin might lead to differences in target site pharmacokinetics. These differences, however, are not related to a difference in target site pharmacodynamics.

FIG. 1.

Time versus total concentration in plasma and unbound concentration in interstitial space fluid profiles for muscle and subcutaneous adipose tissue following administration of a single p.o. dose of 500 mg of ciprofloxacin or a single i.v. dose of 400 mg to healthy volunteers (n = 8). The results are presented as means ± standard errors. The time of drug administration was from 0 to 1 h.

FIG. 2.

Profiles of time versus concentrations in plasma, capillary blood, cantharis-induced skin blister fluid, and saliva following administration of a single p.o. dose of 500 mg of ciprofloxacin (upper panels) or a single i.v. dose of 400 mg over 60 min (lower panels) to healthy volunteers (n = 8). The results are presented as means ± standard errors. The time of drug administration was from 0 to 1 h.

FIG. 3.

Time course of ratios of the ciprofloxacin concentration in the interstitial space fluid of muscle or subcutaneous tissue, saliva, and cantharis-induced skin blister fluid to the concentration in plasma for the experiments shown in Fig. 1. The results are presented as means ± standard errors. The time of drug administration was from 0 to 1 h.

FIG. 4.

Mean time-kill curves (n = 6) for the in vivo pharmacokinetic-in vitro pharmacodynamic simulation model. The in vivo time course of the ciprofloxacin concentration was obtained by measuring the antibiotic concentrations in the interstitial space fluid of subcutaneous adipose tissue for the experiments shown in Fig. 1 after administration of 500 mg of ciprofloxacin p.o. and 400 mg of ciprofloxacin i.v. The in vitro simulation was done with select strains of Enterobacter (▿), K. pneumoniae (○), and S. aureus (▵). ▪, control growth curves; dotted lines, detection limit.