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 mug min/ml versus 2840 mug 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 CLNR (20.1 ml/(min kg) versus 10.5 ml/(min kg)) in rats with liver cirrhosis. The significantly slow CLNR was due to slower hepatic blood flow rate and significantly slower in vitro intrinsic oltipraz disappearance clearance (CLint, 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 mug min/ml versus 812 mug 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 CLint in the rats. (C) 2004 Elsevier B.V. All rights reserved.