Pharmacokinetic Evaluation of Neutrophil Elastase Inhibitor in Sprague-Dawley Rats 9033

Abstract Description Introduction Sivelestat is a neutrophil elastase inhibitor that reduces elastase activation and neutrophil aggregation during inflammatory responses. Our long-term goal is to test whether sivelestat can attenuate polytrauma induced immune-mediated organ dysfunction. The Pharmacokinetic (PK) profile of intravenous administration of sivelestat is not available. The aim is to evaluate the PK of sivelestat to determine the optimal dosing regimen for efficacy studies in rats. Method Sprague-Dawley rats (n = 5) were anesthetized with isoflurane, provided buprenorphine and catheters were inserted into the carotid artery and femoral vein. They received a single intravenous bolus of sivelestat (2 mg/kg) and blood samples were collected at 0, 5, 10, 15, 30, 60, 120, 240, 480, and 720min. The concentration of sivelestat was measured using high performance liquid chromatography– mass spectrometry. PK parameters were calculated by noncompartmental analysis using PK Analix® (Simulations Plus, USA). Results The Cmax is 22.4±7.6µM with a Tmax of 6±2.2min. AUC0-t is 478.8±154.6µM*mins and AUC0-∞ 484.4±158.2µM*mins. Clearance is 0.021±0.0071L⋅min?¹⋅kg?¹, half-life 114.09±65.8min and the volume of distribution 3.08 -1±1. 03L.kg. Conclusion The results indicate that sivelestat is easily absorbed, has short half-life and short Tmax indicating a fast onset of action. These data will be used to determine the most effective and safe dose to be used intravenously in rats in polytrauma treatment studies Funding Sources US Army Medical Research and Development Command (Grant numbers: CO240046 and DM230026) Topic Categories Translational and Interventional Immunology (TI)