Pharmacokinetics and therapeutic effects of oltipraz after consecutive or intermittent oral administration in rats with liver cirrhosis induced by dimethylnitrosamine.
Pharmacokinetics and therapeutic effects of oltipraz were evaluated after consecutive (once per day at 30 mg/kg/day for 7 and 14 days) or intermittent (once per week at 100 mg/kg/week for 1-3 weeks) oral administration to rats with liver cirrhosis induced by dimethylnitrosamine. The AUC of oltipraz was significantly greater in cirrhotic rats than controls (890 compared with 270 microg . min/mL) due to impaired liver function in cirrhotic rats. However, the AUC values after consecutive 7 (421 compared with 753 microg . min/mL) and 14 (309 compared with 821 microg . min/mL) days oral administration of oltipraz in cirrhotic rats were significantly smaller than those in respective vehicle-treated cirrhotic rats. Moreover, the AUC values after intermittent 2 and 3 weeks in cirrhotic rats were also significantly smaller than that in 1 week vehicle-treated cirrhotic rats (2370 and 1690 compared with 4760 microg . min/mL). This could be due to induction of CYP isozymes and considerably greater numbers of normal liver cells in cirrhotic rats by oral administration of oltipraz. Improved liver function by oltipraz in cirrhotic rats was proved by liver microscopy; livers are free of significant fibrosis, although evidence of bridging necrosis is still present in many rats.
Bae
Soo K
SK
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea.
Lee
Shin J
SJ
Kim
Taekrho
T
Kim
Jin W
JW
Lee
Inchul
I
Kim
Sang G
SG
Lee
Myung G
MG
D000284:Administration, Oral; D000477:Alkylating Agents; D000818:Animals; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D003404:Creatinine / Q000378:metabolism; D004128:Dimethylnitrosamine; D006207:Half-Life; D006400:Hematocrit; D008099:Liver / Q000378:metabolism; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000378:metabolism; D008297:Male; D009929:Organ Size / Q000187:drug effects; D011719:Pyrazines / Q000493:pharmacokinetics* / Q000627:therapeutic use* / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D012556:Schistosomicides / Q000493:pharmacokinetics* / Q000627:therapeutic use* / Q000633:toxicity; D013871:Thiones; D013876:Thiophenes
D000477:Alkylating Agents; D011719:Pyrazines; D012556:Schistosomicides; D013871:Thiones; D013876:Thiophenes; C026209:oltipraz; D003404:Creatinine; D004128:Dimethylnitrosamine