Pharmacokinetic changes of oltipraz after intravenous and oral administration to rats with liver cirrhosis induced by dimethylnitrosamine.
Pharmacokinetic changes of oltipraz were investigated after intravenous and oral administration at a dose of 30 mg/kg to control Sprague-Dawley rats and rats with liver cirrhosis induced by dimethylnitrosamine. After intravenous administration in rats with liver cirrhosis, the area under the plasma concentration-time curve from time zero to time infinity (AUC) was significantly greater (1490 microg min/ml versus 2840 microg min/ml) than that in control rats. This was due to significantly slower total body clearance (CL) (20.2 ml/(min kg) versus 10.6 ml/(min kg)) in the rats. The slower CL was due to significantly slower CL(NR) (20.1 ml/(min kg) versus 10.5 ml/(min kg)) in rats with liver cirrhosis. The significantly slow CL(NR) was due to slower hepatic blood flow rate and significantly slower in vitro intrinsic oltipraz disappearance clearance (CL(int), 77.2 ml/min per whole liver versus 11.5 ml/min per whole liver) because the free (unbound in serum proteins) fraction of oltipraz was significantly greater (15.1% versus 31.3%) in the rats. After oral administration in rats with liver cirrhosis, the AUC was also significantly greater (354 microg min/ml versus 812 microg min/ml) and this was not due to increased absorption in the rats. This also could be due to slower hepatic blood flow rate and significantly slower CL(int) in the rats.
Bae
Soo K
SK
Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, San 56-1, Shinlim-Dong, Kwanak-Gu, Seoul 151-742, South Korea.
Lee
Shin J
SJ
Lee
Jang Y
JY
Lee
Youngsoo
Y
Lee
Inchul
I
Kim
Sang G
SG
Lee
Myung G
MG
D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001798:Blood Proteins / Q000378:metabolism; D004128:Dimethylnitrosamine; D007275:Injections, Intravenous; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D011485:Protein Binding; D011719:Pyrazines / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012556:Schistosomicides / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics*; D013871:Thiones; D013876:Thiophenes; D013997:Time Factors; D014018:Tissue Distribution
D001798:Blood Proteins; D011719:Pyrazines; D012556:Schistosomicides; D013871:Thiones; D013876:Thiophenes; C026209:oltipraz; D004128:Dimethylnitrosamine