Pharmacokinetics, biodistribution and toxicology following intravenous and oral administration of DSM-RX78 and EFB-1, two new 2-(2-fluorobenzamido) benzoate-based PDE4 inhibitors, to rats

Abstract

Objectives The aim of this study was to determine the pharmacokinetic profile, biodistribution and toxicity of ethyl 2-(2-fluorobenzamido)benzoate (EFB-1) and methyl 2-(2-fluorobenzamido)benzoate (DSM-RX 78), two phosphodiesterase IV inhibitors, which potently attenuate haemorrhagic shock-induced lung injury in rat. Methods Quantification of DSM-RX78, EFB-1 and 2-(2-fluorobenzamido)benzoate (SMP-3) in plasma was carried out by HPLC. Furthermore, the pharmacokinetics and biodistribution of intravenously (1.0 and 3.0 mg/kg) and orally (40.0 mg/kg) administered DSM-RX78, EFB-1, and SMP-3 were determined in Sprague-Dawley rats. Toxicity and histological analyses were also evaluated herein. Key findings A liquid chromatography method has been developed for the quanification of EFB-1, DSM-RX78 and SMP-3 in rat plasma. The method was sensitive with good linearity (r2 = 0.9990) over a range of 1.56-0.0975 μg/ml. The mean kinetic parameters of DSM-RX 78 and EFB-1 following intravenous administration were as follows: elimination half-life (t 1/2) 8.98 and 8.77 min; clearance (Cl) 24.57 and 22.31 ml/min/kg; AUC 0-∞ 41.76 and 48.03 min mg/l. Conclusions The pharmacokinetics, toxicity and biodistribution of DSM-RX78 and EFB-1 were determined for the first time. The results showed that the pharmacokinetic profiles of DSM-RX78 and EFB-1 were similar, and that EFB-1 had a better safety profile than DSM-RX78. Therefore, EFB-1 was suitable as a lead compound for the development of new agents in the treatment of neutrophilic inflammatory diseases. © 2012. Royal Pharmaceutical Society.