Ketoprofen glucuronidation and bile excretion in carbon tetrachloride and alpha-naphthylisothiocyanate induced hepatic injury rats

• Published in: Toxicology (Amsterdam) 2007-02, Vol.230 (2), p.145-150
• Main Authors: Zhao, Ying, Zhai, Desheng, Chen, Xijing, Yang, Jinnan, Song, Xiangfeng, He, Hui, Yu, Qiaoling, Xing, Yan
• Format: Article
• Language: English
• Subjects: Alanine Transaminase - blood; Alpha-naphthylisothiocyanate; Animals; Anti-Inflammatory Agents, Non-Steroidal - blood; Anti-Inflammatory Agents, Non-Steroidal - pharmacokinetics; Area Under Curve; Bile - metabolism; Bile - secretion; Bile excretion; Bilirubin - blood; Biological and medical sciences; Blood Urea Nitrogen; Carbon tetrachloride; Carbon Tetrachloride Poisoning - metabolism; Chemical and Drug Induced Liver Injury; Emergency; Glucuronidation; Hepatic injury; Histocytochemistry; Isocyanates - toxicity; Ketoprofen; Ketoprofen - analogs & derivatives; Ketoprofen - blood; Ketoprofen - pharmacokinetics; Liver - drug effects; Liver - metabolism; Liver - secretion; Liver Diseases - metabolism; Liver Diseases - pathology; Male; Medical sciences; Microsomes, Liver - drug effects; Microsomes, Liver - metabolism; Naphthalenes - toxicity; Random Allocation; Rats; Rats, Sprague-Dawley; Toxicology
• ISSN: 0300-483X; 1879-3185
• DOI: 10.1016/j.tox.2006.11.008

Abstract A pharmacokinetic study was carried out in rats to investigate the effects of experimental hepatic injury on the liver glucuronidation and bile excretion of ketoprofen (KP) and its glucuronides (KPGs). In vivo, KP (20 mg/kg b.w.) was intravenously administered to carbon tetrachloride (CCl4 ) or alpha-naphthylisothiocyanate (ANIT) induced hepatic injury male rats. Concentrations of KP and its glucuronides (S-KPG and R-KPG) in plasma and bile were determined by RP-HPLC. It was observed that there was significant difference in the accumulative bile excretion of KPGs between the CCl4 intoxicated rats and the normal rats (54 ± 18.3% versus 90 ± 6.9%), while it was extremely inhibited in ANIT intoxicated rats (2.0 ± 3.1% versus 90 ± 6.9%). As the result of reduction of KPGs excreted in bile, the area under the curve (AUC(0–∞) ) of KP and KPGs were higher in blood in CCl4 and ANIT hepatic injury rats than those of the normal rats. Specifically, ANIT caused approximately 10-fold elevation of AUC(0–∞) of plasma S-KPG. In microsomal incubations experiment, the glucuronyltransferase activity was impaired in CCl4 and ANIT intoxicated rats. It suggested that the glucuronyltransferase activity was impaired in CCl4 and ANIT intoxicated rats, while the bile excretion function was suppressed extremely in ANIT intoxicated rats.