Introduction. Acute bacterial endometritis is an uterus opportunist infection common in human and veterinary medicine. The search of local treatments which can be retained in the infection site is a challenge with potential clinical importance. Previous studies showed that the administration of an intrauterine (IU) single dose of the novel controlled release carbomer-ciprofloxacin (Cb-CIP) hydrogel drove to bacterial cure in 63.3, 70 and 85.7% in mares with endometritis (1). The goal of this work was to determine plasmatic and uterine levels of CIP after IU administration of Cb-CIP hydrogel, compared to oral administration of CIP solution (reference), as efficacy and safety indicators. Materials and Methods: Cb-CIP hydrogel was obtained by neutralizing a 0.5% dispersion of Cb with CIP and NaOH (pH=7.01, CIP final concentration: 0.25%) and subjected to autoclave sterilization. In a parallel design 54 rats (Wistar, female, 250 g) were divided in 2 experimental groups. The first group received an IU single dose of Cb-CIP hydrogel (2 mg CIP/Kg,) using a nasogastric tube inserted through the vagina of ether-anesthetized rats. The second group received an intragastric (IG) dose of CIP reference solution. Three animals of each group were sacrificed at 0, 1, 3, 6, 9, 12, 24, 36 and 48 hs post-administration. Blood and uterus samples were processed and quantified by the HPLC-fluorescence method described by Gonzalez et al (2). The statistical analysis was made with one way ANOVA test (p<0.05). Results: Pharmacokinetic parameters are informed in table 1.CIP penetrates well the rat endometrial tissue after both IU or IG administrations. However, after IU administration of the Cb-CIP hydrogel, CIP uterine levels were higher than those obtained after IG administration of CIP reference solution. C_max in uterine tissue after IG administration significantly was higher (p< 0.05) than IG administration. The PK/PD integration (C_max/MIC₉₀) values (table 1) indicated that uterine levels of CIP obtained after IU administration exceeded 2- 3 times the MIC₉₀ for the most pathogenic bacterial organisms in endometritis (3,4), for at least 12 h post-administration. In contrast, IG administration of CIP reference solution produced sub-MIC uterine levels. Besides, plasma levels after IU administration were lower. Discussion and Conclusión: The IU administration of a single dose of Cb-CIP hydrogel produced higher endometrial AUC and Cmax  values of CIP than those values from IG administration of the same dose of CIP reference solution. These levels are above than those reported after intravenous administration of a dose of 5 mg/Kg (3) and are maintained for an extended period of time. Therefore, treatment with Cb-CIP hydrogel could be a more efficient option to treat uterus infections. In addition, the lower plasmatic levels of CIP attained after IU administration suggest a lower risk to present dose-dependent adverse effects. The results obtained underline that IU administration of Cb-CIP hydrogel could be an interesting alternative for the treatment of endometritis in both human and veterinary medicine. 

References

1. Fumuso E, Breda A, Redolatti C, Marinone A, Herrera M, Fernández H, Olivera M,  Manzo R, Sanchez Bruni S. Assessment of safety and efficacy of a novel intrauterine ciprofloxacin sustained release hydrogel formulation in mares with endometritis. 1º Reunion Internacional de Ciencias Farmaceuticas-RICIFA 2010.

2. Gonzalez C, Moreno L, Small J, Jones D, Sanchez Bruni S. A liquid chromatographic method, with fluorometric detection, for the determination of enrofloxacin and ciprofloxacin in plasma and endometrial tissue of mares. Anal Chem Acta 2006;569:227-234.

3. Papich M, Van Camp S, Cole J, Whitacre M D. Pharmacokinetics and endometrial tissue concentrations of enrofloxacin and the metabolite ciprofloxacin after i.v. administration of enrofloxacin to mares. J. vet. Pharmacol. Therap. 2002;25: 343-350.

4. Martinez M, McDermott P, Walke R. Pharmacology of the fluoroquinolones: A perspective for the use in domestic animals. The Veterinary Journal.  2006;172(1): 10-28.

Table 1: pharmacokinetics parameters in plasma and uterine tissue and PK/PD integration of CIP following a single IG (reference solution) and IU (hydrogel) administration in female Wistar rats, at a dose of 2 mg CIP/kg.

^(*)Statistical significance p< 0.05