Physicochemical characterization and pharmacokinetics in broiler chickens of a new recrystallized enrofloxacin hydrochloride dihydrate

Abstract

Enrofloxacin, a key antimicrobial agent in commercial avian medicine, has limited bioavailability (60%). This prompted its chemical manipulation to yield a new solvate-recrystallized enrofloxacin hydrochloride dihydrate entity (enroC ). Its chemical structure was characterized by means of mass spectroscopy, Fourier transformed infrared spectroscopy, X-ray powder diffraction, and thermal analysis. Comparative oral pharmacokinetics (PK) of reference enrofloxacin (enroR ) and enroC in broiler chickens after oral administration revealed noticeable improvements in key parameters and PK/PD ratios. Maximum serum concentration values were 2.61 ± 0.21 and 5.9 ± 0.42 μg/mL for enroR and enroC , respectively; mean residence time was increased from 5.50 ± 0.26 h to 6.20 ± 0.71 h and the relative bioavailability of enroC was 336%. Considering Cmax /MIC and AUC/MIC ratios and the MIC values for a wild-type Escherichia coli O78/H12 (0.25 μg/mL), optimal ratios will only be achieved by enroC (Cmax /MIC = 23.6 and AUC/MIC = 197.7 for enroC ; vs. Cmax /MIC = 10.4 and AUC/MIC = 78.1 for enroR ). Furthermore, enroC may provide in most cases mutant prevention concentrations (Cmax /MIC ≥ 16). Ready solubility of powder enroC in drinking water at concentrations regularly used (0.01%) to provide an additional advantage of enroC in the field. Further development of enroC is warranted before it can be recommended for clinical use in veterinary medicine.

Serum pharmacokinetics and tissue concentrations of a newrecrystallized enrofloxacin hydrochloride-dihydrate in hamsters

“…Failure to attain these ratios has been linked to an increase in bacterial resistance and lack of clinical efficacy (20). Synthesis of a solvate of enrofloxacin (enrofloxacin hydrochloride-dihydrate; enro-C) (13) with improved pharmacokinetics has been advanced as means to obtain improved PK/PD ratios (14,15) and, ideally, to achieve theoretical mutant-preventive concentrations (C MAX ≥ 16 MIC) (21). Enro-C exhibits different physicochemical properties from the parent compound, mainly water solubility (13) and pharmacokinetics, as has been so far shown in broilers (15).…”

“…Synthesis of a solvate of enrofloxacin (enrofloxacin hydrochloride-dihydrate; enro-C) (13) with improved pharmacokinetics has been advanced as means to obtain improved PK/PD ratios (14,15) and, ideally, to achieve theoretical mutant-preventive concentrations (C MAX ≥ 16 MIC) (21). Enro-C exhibits different physicochemical properties from the parent compound, mainly water solubility (13) and pharmacokinetics, as has been so far shown in broilers (15). In this latter case, enro-C somehow improved key PK features, namely AUC 0-¥ , T½b, and C MAX , and consequently PK/PD ratios, that allow the prediction of better clinical outcomes with enro-C as compared to enro R .…”

“…A new solvate of enrofloxacin is already available for research (enrofloxacin hydrochloridedihydrate, enro-C) (14), and it has shown improved PK values in broilers (15). Hence, the aim of this trial was to determine the PK and the PK/PD ratios of enrofloxacin from enro R and from enro-C in Syrian golden hamsters while assessing as pharmacodynamic markers the MIC values for methicillin-resistant Staphylococcus aureus, Leptospira interrogans, and Escherichia coli.…”

Serum and milk concentrations of enrofloxacin in cows intramammarily treated with a new enrofloxacin-polymorph

“…This has been shown for florfenicol in lactating cows, with a three-fold increment in C MAX values (from 2.3 to 6.9 µg/mL) (27). Also, higher C MAX values for enro-C have been shown after oral administration in broiler chickens (12) and after IM administration in hamsters (6). Enro-C can be described as a polymorphic enrofloxacin, and it is not rare to obtain better pharmacokinetics with a re-crystallized polymorph of an active principle (7,26); for example: rifaximin-α, a crystal polymorph, is much more bioavailable than the parent molecule (5).…”

“…However, to the best of our knowledge, no commercial preparations Serum and milk concentrations of enrofloxacin in cows intramammarily treated with a new enrofloxacin-polymorph 1) for this route exist in most countries, and the available products for parenteral administration have a pH at or above 10.4; a fact that makes intramammary administration of the drug rather unadvisable (28). However, a new recrystallized enrofloxacin polymorphic form, enrofloxacin hydrochloride-dihydrate (enro-C) (19), has shown higher water solubility than the parent compound and a superior bioavailability than reference enrofloxacin in broiler chicken (12). As a 1.5% suspension, enro-C exhibits a pH of 5.5, and it does not irritate the mammary gland when intramammarily administered (17).…”