Hepatic and intestinal first-pass effects of a new hepatoprotective agent, YH439, in rats

First-pass effects of YH439 were evaluated after intravenous, intraportal, oral, and intraduodenal administration of the drug, 100 mg/kg body weight, to rats. The first-pass effects of YH439 in the lung and heart seemed to be negligible based on total body clearance values after intravenous and intraportal administration of the drug to rats compared with cardiac output in rats. Approximately 60% of orally and intraduodenally administered YH439 was not absorbed from rat gastrointestinal tract and the F values of YH439 were less than 0.22% after both administration of the drug to rats. Therefore, it could be concluded that approximately 40% of orally and/or intraduodenally administered YH439 could disappeared by hepatic and/or gastrointestinal first-pass effects. The hepatic first-pass effect of YH439 absorbed into the portal vein was approximately 45% (AUC difference between intravenous and intraportal administration) in rats. The AUC0-8hr values of YH439 after oral (18.7 microg min/ml) and intraduodenal (23.4 microg min/ml) administration were significantly smaller than that after intraportal administration (3260 microg min/ml), however, the values were not significantly different between oral and intraduodenal administration, suggesting that the gastric first-pass effect seemed to be negligible and intestinal first-pass effect was considerable in rats. The low F of YH439 in rats could be mainly due to unabsorption (approximately 60%) and hepatic and intestinal first-pass effect (approximately 40%).