The effect of diethyl ether, pentobarbitone and urethane anaesthesia on diflunisal conjugation and disposition in rats

Abstract

1. The disposition of diflunisal (DF) at 10 mg/kg i.v. was investigated over 4 h in bileexteriorized male rats continuously anaesthetized with (a) diethyl ether inhalation (as required), (b) pentobarbitone sodium i.p. (55 mg/kg initially), (c) urethane i.p. (1500 mg/kg initially) or (d) urethane i.v. (750mg/kg initially), and compared to that obtained in conscious rats. 2. Diethyl ether decreased the plasma clearance of DF to about 30% of control values, by inhibition of both glucuronidation and sulphation of DF. 3. Pentobarbitone anaesthesia caused only modest inhibition of DF elimination, with plasma clearance decreased to about 80% of control values. 4. Plasma profiles and biliary recovery of DF and its conjugates were little altered by urethane i.p. anaesthesia, but urinary recovery was low and variable because of the nearanuria produced by urethane via this administration route. 5. Urinary recovery of DF and its conjugates was satisfactory in rats given urethane i.v., but tissue distribution of DF was substantially decreased. 6. Pentobarbitone was considered to interfere least with DF disposition at the 10 mg/kg dose, and was selected as the most suitable anaesthetic agent for ongoing studies of disposition of DF and its conjugates in anaesthetized rats.