Ketoprofen glucuronidation and bile excretion in carbon tetrachloride and alpha-naphthylisothiocyanate induced hepatic injury rats.
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 (20mg/kg b.w.) was intravenously administered to carbon tetrachloride (CCl(4)) 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 CCl(4) 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-infinity))) of KP and KPGs were higher in blood in CCl(4) and ANIT hepatic injury rats than those of the normal rats. Specifically, ANIT caused approximately 10-fold elevation of AUC((0-infinity)) of plasma S-KPG. In microsomal incubations experiment, the glucuronyltransferase activity was impaired in CCl(4) and ANIT intoxicated rats. It suggested that the glucuronyltransferase activity was impaired in CCl(4) and ANIT intoxicated rats, while the bile excretion function was suppressed extremely in ANIT intoxicated rats.
Zhao
Ying
Y
Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu 210009, China.
Zhai
Desheng
D
Chen
Xijing
X
Yang
Jinnan
J
Song
Xiangfeng
X
He
Hui
H
Yu
Qiaoling
Q
Xing
Yan
Y
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000097:blood / Q000493:pharmacokinetics; D019540:Area Under Curve; D001646:Bile / Q000378:metabolism*; D001663:Bilirubin / Q000097:blood; D001806:Blood Urea Nitrogen; D002252:Carbon Tetrachloride Poisoning / Q000378:metabolism*; D056486:Chemical and Drug Induced Liver Injury; D006651:Histocytochemistry; D017953:Isocyanates / Q000633:toxicity*; D007660:Ketoprofen / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008107:Liver Diseases / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D009281:Naphthalenes / Q000633:toxicity*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley
D000894:Anti-Inflammatory Agents, Non-Steroidal; D017953:Isocyanates; D009281:Naphthalenes; C061621:alpha-naphthyl isocyanate; C044223:ketoprofen glucuronide; D007660:Ketoprofen; D000410:Alanine Transaminase; D001663:Bilirubin