Sophie Dautrey

Intestinal elimination of ciprofloxacin in rabbits.

The intestinal transepithelial elimination of ciprofloxacin was studied in a rabbit model. Jejunal, ileal, and cecal segments along with their intact blood vessels were isolated and perfused, and their contents were collected over a 120-min period following administration of a single parenteral dose of 27 mg of ciprofloxacin per kg of body weight. The intestinal elimination rates of ciprofloxacin were 0.126 +/- 0.084, 0.235 +/- 0.22, and 0.11 +/- 0.084 micrograms.min-1.cm-2 for the jejunal, ileal, and cecal segments, respectively. The calculated fractions of ciprofloxacin eliminated were 3.3 mg from the jejunum and 13.8 mg from the ileum, representing 19% of the administered dose. Additional amounts of 2.5 to 3.7 mg or 4.9 to 7.3% of the administered dose were eliminated from the cecum. Elimination was probably not due to a passive diffusion process but rather due to an active transepithelial transport. This intestinal elimination pattern of ciprofloxacin may explain the unusual activity of the fluoroquinolones in modifying the intestinal flora.

Intestinal elimination of sparfloxacin, fleroxacin, and ciprofloxacin in rats.

The intestinal transepithelial elimination of sparfloxacin and fleroxacin was compared with that of ciprofloxacin in a rat model following a single parenteral administration of 25 mg of each of the antibiotics per kg of body weight. All three fluoroquinolones were eliminated through the small intestine. Ciprofloxacin was eliminated in the proximal jejunum at a rate of 1.97 +/- 0.70 micrograms/cm2, while the elimination rates of fleroxacin and sparfloxacin were 0.64 +/- 026 and 0.21 +/- 0.10 micrograms/cm2, respectively, over a 90-min collection period. In the ileum, the elimination rates of ciprofloxacin, fleroxacin, and sparfloxacin over the same period were 1.44 +/- 0.77, 1.00 +/- 0.33, and 0.41 +/- 0.26 micrograms/mc2, respectively. These data suggest that these fluoroquinolones undergo a transepithelial elimination process in the small intestine. This route of elimination may be important in the therapy of bacterial diarrhea.

Influence of Renal Failure on Ciprofloxacin Pharmacokinetics in Rats

ABSTRACT Ciprofloxacin pharmacokinetics have been shown to be modified in patients with renal failure (e.g., the intestinal secretion of ciprofloxacin is increased). This study investigated the influence of renal failure on the pharmacokinetics of ciprofloxacin following oral and parenteral administration to rats of a dose of 50 mg/kg of body weight. After parenteral administration, only renal clearance (CLR) was reduced in nephrectomized rats (5.3 ± 1.4 versus 17.8 ± 4.7 ml/min/kg, P< 0.01, nephrectomized versus control rats). However, nonrenal clearance was increased in nephrectomized rats (32 ± 4 versus 15 ± 5 ml/min/kg, P < 0.01, nephrectomized versus control rats), suggesting compensatory mechanisms for reduced renal function. After oral administration, apparent total clearance and CLR were reduced (P < 0.01) in nephrectomized rats (117 ± 25 and 6.8 ± 4.4 ml/min/kg, respectively) compared with the values for control rats (185 ± 9 and 22.6 ± 5.3 ml/min/kg, respectively) and the area under the concentration-time curve was higher (P < 0.01) for nephrectomized rats (436.3 ± 90.5 mg · min/liter) than for control rats (271.3 ± 14.3 mg · min/liter). Terminal elimination half lives in the two groups remained constant after oral and parenteral administration. These results suggest an increased bioavailability of ciprofloxacin in nephrectomized rats, which was confirmed by a nonlinear mixed-effect model.

Teicoplanin-Containing Cement Spacers for Treatment of Experimental Staphylococcus aureus Joint Prosthesis Infection

ABSTRACT Using a rabbit model of methicillin-resistant Staphylococcus aureus knee-prosthesis infection, we studied the efficacy of teicoplanin cement alone or in combination with systemic intramuscular (i.m.) injections of teicoplanin. Seven days after infection, surgical debridement and removal of the infected prostheses were performed, and five rabbits were randomly assigned to one of five different treatment groups: untreated controls, prosthesis replacement by drug-free cement spacer, prosthesis replacement by teicoplanin-loaded cement spacer (1.2 g of teicoplanin/40 g of cement), i.m. injections of teicoplanin (20 mg/kg of body weight, twice a day for 7 days), or systemic antibiotic treatment combined with teicoplanin-loaded spacers. The most effective regimen combined systemic teicoplanin and antibiotic spacers.

Stereoselectivity of Ofloxacin Intestinal Transport in the Rat

Transintestinal transport of fluoroquinolones is poorly understood. Previous studies have shown saturable absorption of ofloxacin in the rat,Dl and potential and pH-dependent transport of enoxacin in rat intestinal brush borders.f21 Net intestinal secretion of ciprofloxacin has been demonstrated in the rat intestine[31 and in Caco-2 celllayers,l41 and appeared to be an active, saturable process. Sparfloxacin also shows a net secretory flux in the rabbit ileum.fSl To confirm the involvement of transporters in intestinal transfer mechanisms, we examined the stereoselectivity of the absorption and secretion of the chiral fluoroquinolone ofloxacin. Male Sprague-Dawley rats (250 to 350g) were used. After an overnight fast, animals were anaesthetised with urethane. To evaluate the absorption characteristics of ofloxacin, a 30cm intestinal segment, beginning 2cm from the pylorus, was perfused with drug solution (racemic ofloxacin) at various concentrations (0.125, 0.625 and 1.25 mg/rnl) and pH values, at a rate of 0.6 mllmin. Vascularisation of the intestine was preserved. Blood samples of 0.25ml were withdrawn from the portal vein every 10 minutes, as drug concentrations at this site reflect the extent of absorption. To study intestinal secretion, racemic ofloxacin (20 or 40 mg/kg) was injected into the carotid artery. A 30cm segment of intestine was isolated and perfused with saline. Effluent was collected at lO-minute intervals in order to quantify the net secretion of the 2 enantiomers. The bile duct was cannulated in all experiments. High performance liquid chromatography (HPLC) using a bovine serum albumin column was used to assay the 2 ofloxacin isomers. Intestinal absorption is expressed as the area under the curve from 0 to 60 minutes (AUCO-60min), and the amounts secreted by the intestinal segment as /lg/cm2 of intestinal surface. For the same animals, a Students 2-group paired t-test was used to compare the behaviour of the 2 ofloxacin isomers, and an unpaired Students t -test (comparison of results between different animals) was used for all other analyses, with a significance threshold of p < 0.05.