The acute phase response induced by Escherichia coli lipopolysaccharide modifies the pharmacokinetics and metabolism of florfenicol in rabbits

Abstract

The aim of this study was to determine the effect of Escherichia coli lipopolysaccharide (LPS)-induced acute phase response (APR) on the pharmaco-kinetics and biotransformation of florfenicol (FFC) in rabbits. Six rabbits (3.0 ± 0.08 kg body weight (bw)) were distributed through a crossover design with 4 weeks of washout period. Pairs of rabbits similar in bw and sex were assigned to experimental groups: Group 1 (LPS) was treated with three intravenous doses of 1 μg/kg bw of E. coli LPS at intervals of 6 h, and Group 2 (control) was treated with an equivalent volume of saline solution (SS) at the same intervals and frequency of Group 1. At 24 h after the first injection of LPS or SS, an intravenous bolus of 20 mg/kg bw of FFC was administered. Blood samples were collected from the auricular vein before drug administration and at different times between 0.05 and 24.0 h after treatment. FFC and florfenicol-amine (FFC-a) were extracted from the plasma, and their concentrations were determined by high-performance liquid chromatography. A noncompartmental pharmacokinetic model was used for data analysis, and data were compared using the paired Student t-test. The mean values of AUC0-∞ in the endotoxaemic rabbits (26.3 ± 2.7 μg·h/mL) were significantly higher (P < 0.05) than values observed in healthy rabbits (17.2 ± 0.97 μg·h/mL). The total mean plasma clearance (CLT ) decreased from 1228 ± 107.5 mL·h/kg in the control group to 806.4 ± 91.4 mL·h/kg in the LPS-treated rabbits. A significant increase (P < 0.05) in the half-life of elimination was observed in the endotoxaemic rabbits (5.59 ± 1.14 h) compared to the values observed in healthy animals (3.44 ± 0.57 h). In conclusion, the administration of repeated doses of 1 μg/kg E. coli LPS induced an APR in rabbits, producing significant modifications in plasma concentrations of FFC leading to increases in the AUC, terminal half-life and mean residence time (MRT), but a significant decrease in CLT of the drug. As a consequence of the APR induced by LPS, there was a reduction in the metabolic conversion of FFC to their metabolite FFC-a in the liver, suggesting that the mediators released during the APR induced significant inhibitory effects on the hepatic drug-metabolizing enzymes.

Evaluation of cardiac troponin I in serum and myocardium of rabbits with experimentally induced polymicrobial sepsis

“…The results of an experimental inflammation study involving rabbits demonstrated that while plasma CRP concentrations were lower than 10 µg/ml in control rabbits, CRP concentrations started to increase at 6 h after turpentine injection and peaked at 514 µg/ml at 36 h [14]. In another study involving rabbits, after three intravenous injection of LPS at 6-h intervals, the mean serum CRP concentration was 81.4 ± 3.3 µg/ml at 24 h [30]. In our study, the peak serum CRP concentration was 242.70 ± 70.43 µg/ml at 8 h. In EG, the mean serum CRP concentration initially increased at 8 h. Although serum CRP concentration changes were measured to follow the systemic inflammatory response in the present study, serum LDH concentrations quickly increased before serum CRP concentrations increased.…”

Diferencias de especie en las concentraciones plasmáticas y tisulares de florfenicol entre ovinos y conejos

“…Los resultados demuestran que existen diferencias significativas entre estas especies en términos de la distribución del fármaco y su metabolito en plasma y tejidos, lo que indica diferencias de especie en los procesos farmacocinéticos. Se ha estudiado previamente la farmacocinética de FFC y FFC-a posterior a la administración IV de FFC en ovinos (10) y conejos (3). Posterior a la inyección IV de una dosis de FFC de 20 mg/kg, las principales diferencias en la farmacocinética observadas entre estas dos especies se relacionaron con la vida media de eliminación y AUC 0-t -las que fueron más elevadas en ovinos que en conejos.…”

“…La validación de la metodología analítica en tejidos de ovinos fue previamente descrita en nuestro laboratorio por Pérez et al (22), y parámetros como linealidad (r2), recuperación (%), precisión (CV%), límite de detección (LOD) y límite de cuantificación (LOQ) fueron determinados. La validación del método analítico en plasma de conejos fue previamente descrito por Pérez et al (3). La metodología analítica en tejidos de conejos fue validada y entregó valores de recuperación promedio total de FFC y FFC-a de 82.22 ± 5.7% y 81.72 ± 3.8%, respectivamente.…”

“…Su uso ha sido aprobado en rumiantes y cerdos (3) y tiene el potencial de ser usado en especies menores como el conejo (1,2). FFC es altamente lipofílico (4) y se metaboliza en el hígado mediante el sistema citocromo P450 (CYP450) (2,3,4,5). Diversos estudios han demostrado que posterior a su administración, FFC es transformado parcialmente a varios metabolitos, siendo florfenicol amina (FFC-a) el principal de los metabolitos derivados de FFC (6).…”

CLINICAL AND HEMATOLOGICAL CHANGES IN SHEEP INDUCED BY Escherichia coli LIPOPOLYSACCHARIDE

“…There is evidence indicating that the pharmacokinetics of drugs vary during the occurrence of a pathological state or an infection that involves an inflammatory component, therefore, the ability to handle these drugs is diminished (RENTON, 2005), these effects result from the altered expression of certain enzymes of the Cytochrome P450 family (CYP 450) and of drug transport proteins, which are regulated downward (down regulation) during the generation of host defense mechanisms (MORGAN et al, 2008) . This has been demonstrated by different studies where significant modifications in the pharmacokinetics of drugs have been observed between animals treated LPS and control animals (GORALSKI et al, 2003;ELMAS et al, 2006;PÉREZ et al, 2015;PÉREZ et al, 2016).…”