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.
OBJECTIVE
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.


RESULTS
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 (r(2)  = 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 (t½) 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.
Department of Cosmetic Science, Chang Gung University of Science and Technology, Taoyuan, Taiwan.
Jia-You
JY
Fang
Yi-Ting
YT
Liu
Yaw-Bin
YB
Huang
Tai-Long
TL
Pan
Han-Hsiang
HH
Wang
Pei-Wen
PW
Hsieh
D061605:Administration, Intravenous; D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001549:Benzamides / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000633:toxicity; D006207:Half-Life; D055370:Lung Injury / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D058988:Phosphodiesterase 4 Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D012771:Shock, Hemorrhagic / Q000188:drug therapy / Q000378:metabolism; D014018:Tissue Distribution
C560790:2-(2-fluorobenzamido)benzoate ethyl ester; D001549:Benzamides; D058988:Phosphodiesterase 4 Inhibitors; C544338:methyl 2-(2-fluorobenzamido)benzoate