Pharmacokinetics of dexamethasone in pigs

Introduction : Dexamethasone (DEX), a synthetic long-acting corticosteroid is extensively used in veterinary practice as it possesses major anti-inflammatory effects (Ferguson et al., 2009). Gamithromycin (GAMI) is a novel 15-membered semi-synthetic macrolide antibiotic of the azalide subclass recently developed for the treatment and prevention of bovine respiratory disease. Besides the anti-infectious properties, macrolides have frequently been reported to affect various inflammatory processes, such as the production of pro-inflammatory cytokines and mediators (Kanoh and Rubin, 2010). The aim of this study was therefore to determine the pharmacokinetic (PK) parameters of DEX and GAMI in pigs, which can be used in further research to investigate the individual and synergistic immunomodulatory properties of both drugs in a porcine lipopolysaccharide (LPS) inflammation model. Materials and Methods : For DEX, the experiment was performed as a two-way cross-over design. Six 9-week-old male pigs received an injection of 0.3 mg/kg body weight (BW) DEX (Dexa 0.2%®, Kela) intravenously (IV) and intramuscularly (IM). Blood was collected from the jugular vein into EDTA tubes before and post administration (p.a.) at 15, 30, 45 minutes and 1, 2, 4, 6, 8, 12 and 24 h. Plasma was isolated and stored at ≤ -15°C until analysis. For GAMI, twelve 9-week-old male pigs were randomly divided in two groups. The animals received a single injection of 6 mg/kg BW GAMI (Zactran®, Merial), either IV (n = 6) or subcutaneously (SC) (n = 6). Blood was collected from the jugular vein into EDTA tubes before administration; on day 0 at 15, 30 and 45 minutes and 1, 2, 4, 6, 8, 10, 12 and 24 h p.a. and once daily from day 2 to day 14 p.a. (24 h intervals). Plasma was isolated and stored at ≤ -15°C until analysis. Quantitation of DEX and GAMI in the plasma samples was performed using in-house developed and validated LC-MS/MS methods. The pharmacokinetic parameters were analyzed using the software program WinNonlin 6.2.0 (Pharsight). Results and Conclusions : The area under the plasma concentration-time curve (AUC0→∞), absolute bioavailability (F), half-life of absorption and elimination (t1/2abs and t1/2el, respectively), volume of distribution (Vd), clearance (Cl), maximum plasma concentration (Cmax) and time to Cmax (Tmax) were determined for DEX and GAMI. The PK parameters of the innovative macrolide GAMI were compared to those in cattle and foals (Huang et al., 2010; Berghaus et al., 2011). Additionally, the effects of DEX, GAMI and the combination of both drugs on the synthesis and release of TNF-α and IL-6 will be studied in LPS-challenged pigs. Results and conclusions will be presented at the congress. References Ferguson D.C., Dirikolu L., Hoenig M. (2009). Glucocorticoids, Mineralocorticoids, and Adrenolytic drugs. In Veterinary Pharmacology and Therapeutics, 9th Ed. Eds Riviere J.E., Papich M.G. Wiley-Blackwell, Iowa, USA, pp 771-802. Kanoh S. and Rubin B.K. (2010). Mechanisms of Action and Clinical Application of Macrolides as Immunomodulatory Medications. Clinical Microbiology Reviews, 23, 590-615. Huang R.A., Letendre L.T., Banav N., Fischer J., Somerville B. (2011). Pharmacokinetics of gamithromycin in cattle with comparison of plasma and lung tissue concentrations and plasma antibacterial activity. Journal of Veterinary Pharmacology and Therapeutics, 33, 227-237. Berghaus L.J., Giguère S., Sturgill T.L., Bade D., Malinski T.J., Huang R. (2012). Plasma pharmacokinetics, pulmonary distribution, and in vitro activity of gamithromycin in foals. Journal of Veterinary Pharmacology and Therapeutics, 35, 59-65